Publications
| 1. | Franchet, Adrien; Niehus, Sebastian; Caravello, Gaetan; Ferrandon, Dominique: Phosphatidic acid as a limiting host metabolite for the proliferation of the microsporidium Tubulinosema ratisbonensis in Drosophila flies. Nature Microbiology, 4 (4), p. 645, 2019, ISBN: 2058-5276. (type: Article de journal | Résumé | Liens | BibTeX) @article{Franchet2019, title = {Phosphatidic acid as a limiting host metabolite for the proliferation of the microsporidium Tubulinosema ratisbonensis in Drosophila flies}, author = {Adrien Franchet and Sebastian Niehus and Gaetan Caravello and Dominique Ferrandon}, editor = {Nature Publishing Group}, url = {https://www.nature.com/articles/s41564-018-0344-y}, doi = {10.1038/s41564-018-0344-y}, isbn = {2058-5276}, year = {2019}, date = {2019-01-28}, journal = {Nature Microbiology}, volume = {4}, number = {4}, pages = {645}, abstract = {A Drosophila melanogaster systemic infection model for the microsporidian Tubulinosema ratisbonensis reveals that the parasite hijacks host phosphatidic acid, which is a limiting precursor for synthesis of parasite membranes and therefore proliferation.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A Drosophila melanogaster systemic infection model for the microsporidian Tubulinosema ratisbonensis reveals that the parasite hijacks host phosphatidic acid, which is a limiting precursor for synthesis of parasite membranes and therefore proliferation. |
| 2. | Goto, Akira; Okado, Kiyoshi; Martins, Nelson; Cai, Hua; Barbier, Vincent; Lamiable, Olivier; Troxler, Laurent; Santiago, Estelle; Kuhn, Lauriane; Paik, Donggi; Silverman, Neal; Holleufer, Andreas; Hartmann, Rune; Liu, Jiyong; Peng, Tao; Hoffmann, Jules A; Meignin, Carine; Daeffler, Laurent; Imler, Jean-Luc: The Kinase IKKβ Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila. Immunity, (49), p. 225-234, 2018. (type: Article de journal | Résumé | Liens | BibTeX) @article{Goto2018, title = {The Kinase IKKβ Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila}, author = {Akira Goto and Kiyoshi Okado and Nelson Martins and Hua Cai and Vincent Barbier and Olivier Lamiable and Laurent Troxler and Estelle Santiago and Lauriane Kuhn and Donggi Paik and Neal Silverman and Andreas Holleufer and Rune Hartmann and Jiyong Liu and Tao Peng and Jules A. Hoffmann and Carine Meignin and Laurent Daeffler and Jean-Luc Imler}, editor = {Elsevier Inc.}, url = {https://doi.org/10.1016/j.immuni.2018.07.013}, doi = {j.immuni.2018.07.013}, year = {2018}, date = {2018-08-21}, journal = {Immunity}, number = {49}, pages = {225-234}, abstract = {Antiviral immunity in Drosophila involves RNA interference and poorly characterized inducible responses. Here, we showed that two components of the IMD pathway, the kinase dIKKβ and the transcription factor Relish, were required to control infection by two picorna-like viruses. We identified a set of genes induced by viral infection and regulated by dIKKβ and Relish, which included an ortholog of STING. We showed that dSTING participated in the control of infection by picorna-like viruses, acting upstream of dIKKβ to regulate expression of Nazo, an antiviral factor. Our data reveal an antiviral function for STING in an animal model devoid of interferons and suggest an evolutionarily ancient role for this molecule in antiviral immunity.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Antiviral immunity in Drosophila involves RNA interference and poorly characterized inducible responses. Here, we showed that two components of the IMD pathway, the kinase dIKKβ and the transcription factor Relish, were required to control infection by two picorna-like viruses. We identified a set of genes induced by viral infection and regulated by dIKKβ and Relish, which included an ortholog of STING. We showed that dSTING participated in the control of infection by picorna-like viruses, acting upstream of dIKKβ to regulate expression of Nazo, an antiviral factor. Our data reveal an antiviral function for STING in an animal model devoid of interferons and suggest an evolutionarily ancient role for this molecule in antiviral immunity. |
| 3. | Haller, Samantha; Franchet, Adrien; Hakkim, A; Chen, J; Drenkard, E; Yu, S; Schirmeier, Steffi; Li, Zi; Martins, Nelson; Ausubel, FM; Liégeois, Samuel; Ferrandon, Dominique: Quorum-sensing regulator RhlR but not its autoinducer RhlI enables Pseudomonas to evade opsonization. EMBO Reports, 2018. (type: Article de journal | Liens | BibTeX) @article{S2018, title = {Quorum-sensing regulator RhlR but not its autoinducer RhlI enables Pseudomonas to evade opsonization}, author = {Samantha Haller and Adrien Franchet and A Hakkim and J Chen and E Drenkard and S Yu and Steffi Schirmeier and Zi Li and Nelson Martins and FM Ausubel and Samuel Liégeois and Dominique Ferrandon }, url = {http://embor.embopress.org/content/early/2018/03/09/embr.201744880}, doi = {10.15252/embr.201744880}, year = {2018}, date = {2018-03-09}, journal = {EMBO Reports}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 4. | Issa, Najwa; Guillaumot, Nina; Lauret, Emilie; Matt, Nicolas; Scaeffer-Reiss, Christine; Dorsselaer, Alain Van; Reichhart, Jean-Marc; Veillard, Florian: The circulating protease Persephone is an immune sensor for microbial proteolytic activities upstream of the Drosophila Toll pathway.. Molecular Cell, 69 (4), p. 539-550, 2018, ISSN: 1097-2765. (type: Article de journal | Résumé | Liens | BibTeX) @article{Issa2018, title = {The circulating protease Persephone is an immune sensor for microbial proteolytic activities upstream of the Drosophila Toll pathway.}, author = {Najwa Issa and Nina Guillaumot and Emilie Lauret and Nicolas Matt and Christine Scaeffer-Reiss and Alain Van Dorsselaer and Jean-Marc Reichhart and Florian Veillard}, url = {http://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30058-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276518300583%3Fshowall%3Dtrue}, doi = {10.1016/j.molcel.2018.01.029}, issn = {1097-2765}, year = {2018}, date = {2018-02-15}, journal = {Molecular Cell}, volume = {69}, number = {4}, pages = {539-550}, abstract = {Microbial or endogenous molecular patterns as well as pathogen functional features can activate innate immune systems. Whereas detection of infection by pattern recognition receptors has been investigated in details, sensing of virulence factors activities remains less characterized. In Drosophila, genetic evidences indicate that the serine protease Persephone belongs to a danger pathway activated by abnormal proteolytic activities to induce Toll signaling. However, neither the activation mechanism of this pathway nor its specificity has been determined. Here, we identify a unique region in the pro-domain of Persephone that functions as bait for exogenous proteases independently of their origin, type, or specificity. Cleavage in this bait region constitutes the first step of a sequential activation and licenses the subsequent maturation of Persephone to the endogenous cysteine cathepsin 26-29-p. Our results establish Persephone itself as an immune receptor able to sense a broad range of microbes through virulence factor activities rather than molecular patterns.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Microbial or endogenous molecular patterns as well as pathogen functional features can activate innate immune systems. Whereas detection of infection by pattern recognition receptors has been investigated in details, sensing of virulence factors activities remains less characterized. In Drosophila, genetic evidences indicate that the serine protease Persephone belongs to a danger pathway activated by abnormal proteolytic activities to induce Toll signaling. However, neither the activation mechanism of this pathway nor its specificity has been determined. Here, we identify a unique region in the pro-domain of Persephone that functions as bait for exogenous proteases independently of their origin, type, or specificity. Cleavage in this bait region constitutes the first step of a sequential activation and licenses the subsequent maturation of Persephone to the endogenous cysteine cathepsin 26-29-p. Our results establish Persephone itself as an immune receptor able to sense a broad range of microbes through virulence factor activities rather than molecular patterns. |
| 5. | Ferreira, Flávia Viana; Aguiar, Eric Roberto Guimarães Rocha; Olmo, Roenick Proveti; de Oliveira, Karla Pollyanna Vieira; Silva, Emanuele Guimarães; Sant'Anna, Maurício Roberto Viana; de Gontijo, Nelder Figueiredo; Kroon, Erna Geessien; Imler, Jean-Luc; Marques, João Trindade: The small non-coding RNA response to virus infection in the Leishmania vector Lutzomyia longipalpis. PLoS Negl Trop Dis, 12 (6), p. e0006569, 2018, ISSN: 1935-2735. (type: Article de journal | Résumé | Liens | BibTeX) @article{ferreira_small_2018, title = {The small non-coding RNA response to virus infection in the Leishmania vector Lutzomyia longipalpis}, author = {Flávia Viana Ferreira and Eric Roberto Guimarães Rocha Aguiar and Roenick Proveti Olmo and Karla Pollyanna Vieira de Oliveira and Emanuele Guimarães Silva and Maurício Roberto Viana Sant'Anna and Nelder Figueiredo de Gontijo and Erna Geessien Kroon and Jean-Luc Imler and João Trindade Marques}, doi = {10.1371/journal.pntd.0006569}, issn = {1935-2735}, year = {2018}, date = {2018-01-01}, journal = {PLoS Negl Trop Dis}, volume = {12}, number = {6}, pages = {e0006569}, abstract = {Sandflies are well known vectors for Leishmania but also transmit a number of arthropod-borne viruses (arboviruses). Few studies have addressed the interaction between sandflies and arboviruses. RNA interference (RNAi) mechanisms utilize small non-coding RNAs to regulate different aspects of host-pathogen interactions. The small interfering RNA (siRNA) pathway is a broad antiviral mechanism in insects. In addition, at least in mosquitoes, another RNAi mechanism mediated by PIWI interacting RNAs (piRNAs) is activated by viral infection. Finally, endogenous microRNAs (miRNA) may also regulate host immune responses. Here, we analyzed the small non-coding RNA response to Vesicular stomatitis virus (VSV) infection in the sandfly Lutzoymia longipalpis. We detected abundant production of virus-derived siRNAs after VSV infection in adult sandflies. However, there was no production of virus-derived piRNAs and only mild changes in the expression of vector miRNAs in response to infection. We also observed abundant production of virus-derived siRNAs against two other viruses in Lutzomyia Lulo cells. Together, our results suggest that the siRNA but not the piRNA pathway mediates an antiviral response in sandflies. In agreement with this hypothesis, pre-treatment of cells with dsRNA against VSV was able to inhibit viral replication while knock-down of the central siRNA component, Argonaute-2, led to increased virus levels. Our work begins to elucidate the role of RNAi mechanisms in the interaction between L. longipalpis and viruses and should also open the way for studies with other sandfly-borne pathogens.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Sandflies are well known vectors for Leishmania but also transmit a number of arthropod-borne viruses (arboviruses). Few studies have addressed the interaction between sandflies and arboviruses. RNA interference (RNAi) mechanisms utilize small non-coding RNAs to regulate different aspects of host-pathogen interactions. The small interfering RNA (siRNA) pathway is a broad antiviral mechanism in insects. In addition, at least in mosquitoes, another RNAi mechanism mediated by PIWI interacting RNAs (piRNAs) is activated by viral infection. Finally, endogenous microRNAs (miRNA) may also regulate host immune responses. Here, we analyzed the small non-coding RNA response to Vesicular stomatitis virus (VSV) infection in the sandfly Lutzoymia longipalpis. We detected abundant production of virus-derived siRNAs after VSV infection in adult sandflies. However, there was no production of virus-derived piRNAs and only mild changes in the expression of vector miRNAs in response to infection. We also observed abundant production of virus-derived siRNAs against two other viruses in Lutzomyia Lulo cells. Together, our results suggest that the siRNA but not the piRNA pathway mediates an antiviral response in sandflies. In agreement with this hypothesis, pre-treatment of cells with dsRNA against VSV was able to inhibit viral replication while knock-down of the central siRNA component, Argonaute-2, led to increased virus levels. Our work begins to elucidate the role of RNAi mechanisms in the interaction between L. longipalpis and viruses and should also open the way for studies with other sandfly-borne pathogens. |
| 6. | Kuhn, Lauriane; Majzoub, Karim; Einhorn, Evelyne; Chicher, Johana; Pompon, Julien; Imler, Jean-Luc; Hammann, Philippe; Meignin, Carine: Definition of a RACK1 Interaction Network in Drosophila melanogaster Using SWATH-MS. G3 (Bethesda), 2017, ISSN: 2160-1836. (type: Article de journal | Résumé | Liens | BibTeX) @article{kuhn_definition_2017, title = {Definition of a RACK1 Interaction Network in Drosophila melanogaster Using SWATH-MS}, author = { Lauriane Kuhn and Karim Majzoub and Evelyne Einhorn and Johana Chicher and Julien Pompon and Jean-Luc Imler and Philippe Hammann and Carine Meignin}, doi = {10.1534/g3.117.042564}, issn = {2160-1836}, year = {2017}, date = {2017-12-31}, journal = {G3 (Bethesda)}, abstract = {Receptor for Activated C kinase 1 (RACK1) is a scaffold protein that has been found in association with several signaling complexes, and with the 40S subunit of the ribosome. Using the model organism Drosophila melanogaster, we recently showed that RACK1 is required at the ribosome for IRES-mediated translation of viruses. Here, we report a proteomic characterization of the interactome of RACK1 in Drosophila S2 cells. We carried out Label-Free quantitation using both Data-Dependent and Data-Independent Acquisition and observed a significant advantage for the Sequential Window Acquisition of all THeoretical fragment-ion spectra (SWATH) method both in terms of identification of interactants and quantification of low abundance proteins. These data represent the first SWATH spectral library available for Drosophila and will be a useful resource for the community. A total of 52 interacting proteins were identified, including several molecules involved in translation such as structural components of the ribosome, factors regulating translation initiation or elongation and RNA binding proteins. Among these 52 proteins, 15 were identified as partners by the SWATH strategy only. Interestingly, these 15 proteins are significantly enriched for the functions translation and nucleic acid binding. This enrichment reflects the engagement of RACK1 at the ribosome and highlights the added value of SWATH analysis. A functional screen did not reveal any protein sharing the interesting properties of RACK1, which is required for IRES-dependent translation and not essential for cell viability. Intriguingly however, 10 of the RACK1 partners identified restrict replication of Cricket paralysis virus, an IRES-containing virus.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Receptor for Activated C kinase 1 (RACK1) is a scaffold protein that has been found in association with several signaling complexes, and with the 40S subunit of the ribosome. Using the model organism Drosophila melanogaster, we recently showed that RACK1 is required at the ribosome for IRES-mediated translation of viruses. Here, we report a proteomic characterization of the interactome of RACK1 in Drosophila S2 cells. We carried out Label-Free quantitation using both Data-Dependent and Data-Independent Acquisition and observed a significant advantage for the Sequential Window Acquisition of all THeoretical fragment-ion spectra (SWATH) method both in terms of identification of interactants and quantification of low abundance proteins. These data represent the first SWATH spectral library available for Drosophila and will be a useful resource for the community. A total of 52 interacting proteins were identified, including several molecules involved in translation such as structural components of the ribosome, factors regulating translation initiation or elongation and RNA binding proteins. Among these 52 proteins, 15 were identified as partners by the SWATH strategy only. Interestingly, these 15 proteins are significantly enriched for the functions translation and nucleic acid binding. This enrichment reflects the engagement of RACK1 at the ribosome and highlights the added value of SWATH analysis. A functional screen did not reveal any protein sharing the interesting properties of RACK1, which is required for IRES-dependent translation and not essential for cell viability. Intriguingly however, 10 of the RACK1 partners identified restrict replication of Cricket paralysis virus, an IRES-containing virus. |
| 7. | Patrnogic, Jelena; Leclerc, Vincent: The serine protease homolog spheroide is involved in sensing of pathogenic Gram-positive bacteria. PLoS One, 12 (12), 2017. (type: Article de journal | Résumé | Liens | BibTeX) @article{Jelena2017, title = {The serine protease homolog spheroide is involved in sensing of pathogenic Gram-positive bacteria}, author = {Jelena Patrnogic and Vincent Leclerc}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718610/}, doi = {10.1371/journal.pone.0188339}, year = {2017}, date = {2017-12-06}, journal = {PLoS One}, volume = {12}, number = {12}, abstract = {In Drosophila, recognition of pathogens such as Gram-positive bacteria and fungi triggers the activation of proteolytic cascades and the subsequent activation of the Toll pathway. This response can be achieved by either detection of pathogen associated molecular patterns or by sensing microbial proteolytic activities ("danger signals"). Previous data suggested that certain serine protease homologs (serine protease folds that lack an active catalytic triad) could be involved in the pathway. We generated a null mutant of the serine protease homolog spheroide (sphe). These mutant flies are susceptible to Enterococcus faecalis infection and unable to fully activate the Toll pathway. Sphe is required to activate the Toll pathway after challenge with pathogenic Gram-Positive bacteria. Sphe functions in the danger signal pathway, downstream or at the level of Persephone.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In Drosophila, recognition of pathogens such as Gram-positive bacteria and fungi triggers the activation of proteolytic cascades and the subsequent activation of the Toll pathway. This response can be achieved by either detection of pathogen associated molecular patterns or by sensing microbial proteolytic activities ("danger signals"). Previous data suggested that certain serine protease homologs (serine protease folds that lack an active catalytic triad) could be involved in the pathway. We generated a null mutant of the serine protease homolog spheroide (sphe). These mutant flies are susceptible to Enterococcus faecalis infection and unable to fully activate the Toll pathway. Sphe is required to activate the Toll pathway after challenge with pathogenic Gram-Positive bacteria. Sphe functions in the danger signal pathway, downstream or at the level of Persephone. |
| 8. | Gross, Lauriane; Vicens, Quentin; Einhorn, Evelyne; Noireterre, Audrey; Schaeffer, Laure; Kuhn, Lauriane; Imler, Jean-Luc; Eriani, Gilbert; Meignin, Carine; Martin, Franck: The IRES5'UTR of the dicistrovirus cricket paralysis virus is a type III IRES containing an essential pseudoknot structure. Nucleic Acids Research, 45 (15), p. 8993–9004, 2017, ISSN: 1362-4962. (type: Article de journal | Résumé | Liens | BibTeX) @article{gross_ires5utr_2017, title = {The IRES5'UTR of the dicistrovirus cricket paralysis virus is a type III IRES containing an essential pseudoknot structure}, author = { Lauriane Gross and Quentin Vicens and Evelyne Einhorn and Audrey Noireterre and Laure Schaeffer and Lauriane Kuhn and Jean-Luc Imler and Gilbert Eriani and Carine Meignin and Franck Martin}, doi = {10.1093/nar/gkx622}, issn = {1362-4962}, year = {2017}, date = {2017-01-01}, journal = {Nucleic Acids Research}, volume = {45}, number = {15}, pages = {8993--9004}, abstract = {Cricket paralysis virus (CrPV) is a dicistrovirus. Its positive-sense single-stranded RNA genome contains two internal ribosomal entry sites (IRESs). The 5' untranslated region (5'UTR) IRES5'UTR mediates translation of non-structural proteins encoded by ORF1 whereas the well-known intergenic region (IGR) IRESIGR is required for translation of structural proteins from open reading frame 2 in the late phase of infection. Concerted action of both IRES is essential for host translation shut-off and viral translation. IRESIGR has been extensively studied, in contrast the IRES5'UTR remains largely unexplored. Here, we define the minimal IRES element required for efficient translation initiation in drosophila S2 cell-free extracts. We show that IRES5'UTR promotes direct recruitment of the ribosome on the cognate viral AUG start codon without any scanning step, using a Hepatitis-C virus-related translation initiation mechanism. Mass spectrometry analysis revealed that IRES5'UTR recruits eukaryotic initiation factor 3, confirming that it belongs to type III class of IRES elements. Using Selective 2'-hydroxyl acylation analyzed by primer extension and DMS probing, we established a secondary structure model of 5'UTR and of the minimal IRES5'UTR. The IRES5'UTR contains a pseudoknot structure that is essential for proper folding and ribosome recruitment. Overall, our results pave the way for studies addressing the synergy and interplay between the two IRES from CrPV.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Cricket paralysis virus (CrPV) is a dicistrovirus. Its positive-sense single-stranded RNA genome contains two internal ribosomal entry sites (IRESs). The 5' untranslated region (5'UTR) IRES5'UTR mediates translation of non-structural proteins encoded by ORF1 whereas the well-known intergenic region (IGR) IRESIGR is required for translation of structural proteins from open reading frame 2 in the late phase of infection. Concerted action of both IRES is essential for host translation shut-off and viral translation. IRESIGR has been extensively studied, in contrast the IRES5'UTR remains largely unexplored. Here, we define the minimal IRES element required for efficient translation initiation in drosophila S2 cell-free extracts. We show that IRES5'UTR promotes direct recruitment of the ribosome on the cognate viral AUG start codon without any scanning step, using a Hepatitis-C virus-related translation initiation mechanism. Mass spectrometry analysis revealed that IRES5'UTR recruits eukaryotic initiation factor 3, confirming that it belongs to type III class of IRES elements. Using Selective 2'-hydroxyl acylation analyzed by primer extension and DMS probing, we established a secondary structure model of 5'UTR and of the minimal IRES5'UTR. The IRES5'UTR contains a pseudoknot structure that is essential for proper folding and ribosome recruitment. Overall, our results pave the way for studies addressing the synergy and interplay between the two IRES from CrPV. |
| 9. | Chamy, Laure El; Matt, Nicolas; Reichhart, Jean-Marc: Advances in Myeloid-Like Cell Origins and Functions in the Model Organism Drosophila melanogaster. Microbiology Spectrum, 5 (1), 2017, ISSN: 2165-0497. (type: Article de journal | Liens | BibTeX) @article{Chamy2017, title = {Advances in Myeloid-Like Cell Origins and Functions in the Model Organism Drosophila melanogaster}, author = { Laure El Chamy and Nicolas Matt and Jean-Marc Reichhart}, url = {http://www.asmscience.org/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0038-2016}, doi = {10.1128/microbiolspec.MCHD-0038-2016}, issn = {2165-0497}, year = {2017}, date = {2017-01-01}, urldate = {2017-07-12}, journal = {Microbiology Spectrum}, volume = {5}, number = {1}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 10. | Koltun, Bella; Shackelford, Eliza; Bonnay, François; Matt, Nicolas; Reichhart, Jean-Marc; Orian, Amir: The SUMO-targeted ubiquitin ligase, Dgrn, is essential for Drosophila innate immunity. The International Journal of Developmental Biology, 61 (3-4-5), p. 319–327, 2017, ISSN: 0214-6282. (type: Article de journal | Liens | BibTeX) @article{koltun_sumo-targeted_2017, title = {The SUMO-targeted ubiquitin ligase, Dgrn, is essential for Drosophila innate immunity}, author = { Bella Koltun and Eliza Shackelford and François Bonnay and Nicolas Matt and Jean-Marc Reichhart and Amir Orian}, url = {http://www.intjdevbiol.com/paper.php?doi=160250ao}, doi = {10.1387/ijdb.160250ao}, issn = {0214-6282}, year = {2017}, date = {2017-01-01}, urldate = {2017-07-12}, journal = {The International Journal of Developmental Biology}, volume = {61}, number = {3-4-5}, pages = {319--327}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 11. | Mussabekova, Assel; Daeffler, Laurent; Imler, Jean-Luc: Innate and intrinsic antiviral immunity in Drosophila. Cell. Mol. Life Sci., 2017, ISSN: 1420-9071. (type: Article de journal | Résumé | Liens | BibTeX) @article{mussabekova_innate_2017, title = {Innate and intrinsic antiviral immunity in Drosophila}, author = { Assel Mussabekova and Laurent Daeffler and Jean-Luc Imler}, doi = {10.1007/s00018-017-2453-9}, issn = {1420-9071}, year = {2017}, date = {2017-01-01}, journal = {Cell. Mol. Life Sci.}, abstract = {The fruit fly Drosophila melanogaster has been a valuable model to investigate the genetic mechanisms of innate immunity. Initially focused on the resistance to bacteria and fungi, these studies have been extended to include antiviral immunity over the last decade. Like all living organisms, insects are continually exposed to viruses and have developed efficient defense mechanisms. We review here our current understanding on antiviral host defense in fruit flies. A major antiviral defense in Drosophila is RNA interference, in particular the small interfering (si) RNA pathway. In addition, complex inducible responses and restriction factors contribute to the control of infections. Some of the genes involved in these pathways have been conserved through evolution, highlighting loci that may account for susceptibility to viral infections in humans. Other genes are not conserved and represent species-specific innovations.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The fruit fly Drosophila melanogaster has been a valuable model to investigate the genetic mechanisms of innate immunity. Initially focused on the resistance to bacteria and fungi, these studies have been extended to include antiviral immunity over the last decade. Like all living organisms, insects are continually exposed to viruses and have developed efficient defense mechanisms. We review here our current understanding on antiviral host defense in fruit flies. A major antiviral defense in Drosophila is RNA interference, in particular the small interfering (si) RNA pathway. In addition, complex inducible responses and restriction factors contribute to the control of infections. Some of the genes involved in these pathways have been conserved through evolution, highlighting loci that may account for susceptibility to viral infections in humans. Other genes are not conserved and represent species-specific innovations. |
| 12. | Volohonsky, Gloria; Hopp, Ann-Katrin; Saenger, Mélanie; Soichot, Julien; Scholze, Heidi; Boch, Jens; Blandin, Stéphanie A; Marois, Eric: Transgenic Expression of the Anti-parasitic Factor TEP1 in the Malaria Mosquito Anopheles gambiae. PLOS Pathogens, 13 (1), p. e1006113, 2017, ISSN: 1553-7374. (type: Article de journal | Liens | BibTeX) @article{volohonsky_transgenic_2017, title = {Transgenic Expression of the Anti-parasitic Factor TEP1 in the Malaria Mosquito Anopheles gambiae}, author = { Gloria Volohonsky and Ann-Katrin Hopp and Mélanie Saenger and Julien Soichot and Heidi Scholze and Jens Boch and Stéphanie A. Blandin and Eric Marois}, editor = {Vernick, Kenneth D}, url = {http://dx.plos.org/10.1371/journal.ppat.1006113}, doi = {10.1371/journal.ppat.1006113}, issn = {1553-7374}, year = {2017}, date = {2017-01-01}, urldate = {2017-02-01}, journal = {PLOS Pathogens}, volume = {13}, number = {1}, pages = {e1006113}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 13. | Lee, Kwang-Zin; Lestradet, Matthieu; Socha, Catherine; Schirmeier, Stefanie; Schmitz, Antonin; Spenlé, Caroline; Lefebvre, Olivier; Keime, Céline; Yamba, Wennida M.; Bou Aoun, Richard; Liegeois, Samuel; Schwab, Yannick; Simon-Assmann, Patricia; Dalle, Frédéric; Ferrandon, Dominique: Enterocyte Purge and Rapid Recovery Is a Resilience Reaction of the Gut Epithelium to Pore-Forming Toxin Attack. Cell Host & Microbe, 2016, ISSN: 1931-3128. (type: Article de journal | Résumé | Liens | BibTeX) @article{Lee2016, title = {Enterocyte Purge and Rapid Recovery Is a Resilience Reaction of the Gut Epithelium to Pore-Forming Toxin Attack}, author = { Kwang-Zin Lee and Matthieu Lestradet and Catherine Socha and Stefanie Schirmeier and Antonin Schmitz and Caroline Spenlé and Olivier Lefebvre and Céline Keime and Wennida M. Yamba and Richard Bou Aoun and Samuel Liegeois and Yannick Schwab and Patricia Simon-Assmann and Frédéric Dalle and Dominique Ferrandon}, editor = {L. Abate}, url = {http://www.sciencedirect.com/science/article/pii/S193131281630436X}, doi = {10.1016/j.chom.2016.10.010}, issn = {1931-3128}, year = {2016}, date = {2016-11-23}, urldate = {2016-11-25}, journal = {Cell Host & Microbe}, abstract = {Summary Besides digesting nutrients, the gut protects the host against invasion by pathogens. Enterocytes may be subjected to damage by both microbial and host defensive responses, causing their death. Here, we report a rapid epithelial response that alleviates infection stress and protects the enterocytes from the action of microbial virulence factors. Intestinal epithelia exposed to hemolysin, a pore-forming toxin secreted by Serratia marcescens, undergo an evolutionarily conserved process of thinning followed by the recovery of their initial thickness within a few hours. In response to hemolysin attack, Drosophila melanogaster enterocytes extrude most of their apical cytoplasm, including damaged organelles such as mitochondria, yet do not lyse. We identify two secreted peptides, the expression of which requires CyclinJ, that mediate the recovery phase in which enterocytes regain their original shape and volume. Epithelial thinning and recovery constitute a fast and efficient response to intestinal infections, with pore-forming toxins acting as alarm signals.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Summary Besides digesting nutrients, the gut protects the host against invasion by pathogens. Enterocytes may be subjected to damage by both microbial and host defensive responses, causing their death. Here, we report a rapid epithelial response that alleviates infection stress and protects the enterocytes from the action of microbial virulence factors. Intestinal epithelia exposed to hemolysin, a pore-forming toxin secreted by Serratia marcescens, undergo an evolutionarily conserved process of thinning followed by the recovery of their initial thickness within a few hours. In response to hemolysin attack, Drosophila melanogaster enterocytes extrude most of their apical cytoplasm, including damaged organelles such as mitochondria, yet do not lyse. We identify two secreted peptides, the expression of which requires CyclinJ, that mediate the recovery phase in which enterocytes regain their original shape and volume. Epithelial thinning and recovery constitute a fast and efficient response to intestinal infections, with pore-forming toxins acting as alarm signals. |
| 14. | Ehrhardt, Katharina; Deregnaucourt, Christiane; Goetz, Alice-Anne; Tzanova, Tzvetomira; Gallo, Valentina; Arese, Paolo; Pradines, Bruno; Adjalley, Sophie H; Bagrel, Denyse; Blandin, Stephanie A; Lanzer, Michael; Davioud-Charvet, Elisabeth: The redox-cycler plasmodione is a fast acting antimalarial lead compound with pronounced activity against sexual and early asexual blood-stage parasites. Antimicrob. Agents Chemother., 60 (9), p. 5146-5158 , 2016, ISSN: 1098-6596. (type: Article de journal | Résumé | Liens | BibTeX) @article{ehrhardt_redox-cycler_2016, title = {The redox-cycler plasmodione is a fast acting antimalarial lead compound with pronounced activity against sexual and early asexual blood-stage parasites}, author = { Katharina Ehrhardt and Christiane Deregnaucourt and Alice-Anne Goetz and Tzvetomira Tzanova and Valentina Gallo and Paolo Arese and Bruno Pradines and Sophie H. Adjalley and Denyse Bagrel and Stephanie A. Blandin and Michael Lanzer and Elisabeth Davioud-Charvet}, url = {http://aac.asm.org/content/60/9/5146}, doi = {10.1128/AAC.02975-15}, issn = {1098-6596}, year = {2016}, date = {2016-09-01}, journal = {Antimicrob. Agents Chemother.}, volume = {60}, number = {9}, pages = { 5146-5158 }, abstract = {Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox-cyclers - a strategy that is broadly recognized for the development of new antimalarial agents. Here, we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intra-erythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intra-erythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common resistance mechanisms to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a fast killing speed as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that it is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox-cyclers - a strategy that is broadly recognized for the development of new antimalarial agents. Here, we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intra-erythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intra-erythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common resistance mechanisms to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a fast killing speed as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that it is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents. |
| 15. | Paro, Simona; Imler, Jean-Luc: Encyclopedia of Immunobiology. Ratcliffe, M (Ed.): 1 , Chapitre “Immunity in insects”, p. 454-461, Elsevier, 2016. (type: Book Chapter | BibTeX) @inbook{Paro0000, title = {Encyclopedia of Immunobiology}, author = {Simona Paro and Jean-Luc Imler}, editor = {M. Ratcliffe}, year = {2016}, date = {2016-08-01}, volume = {1}, pages = {454-461}, publisher = {Elsevier}, chapter = {“Immunity in insects”}, keywords = {}, pubstate = {published}, tppubtype = {inbook} } |
| 16. | Boujard, Daniel; Leclerc, Vincent; Vincent, Stéphane: Biologie du développement. Editions Dunod, 2016, ISBN: 978-2-10-072085-9. (type: Livre | Résumé | Liens | BibTeX) @book{leclerc2016, title = {Biologie du développement}, author = {Daniel Boujard and Vincent Leclerc and Stéphane Vincent}, editor = {Editions Dunod}, url = {https://www.dunod.com/sciences-techniques/biologie-du-developpement}, isbn = {978-2-10-072085-9}, year = {2016}, date = {2016-06-01}, booktitle = {Biologie du développement}, pages = {304}, edition = {Editions Dunod}, crossref = {EAN: 9782100720859}, abstract = {La biologie du développement étudie les phénomènes qui permettent le passage d’un œuf à un organisme adulte. Cette discipline a beaucoup évolué ces dernières années avec l'essor des nouvelles techniques d’imagerie in vivo, des « omiques » et des techniques de transgénèse. Aux progrès technologiques s’ajoutent les avancées importantes en génétique et épigénétique, tout cela permettant d’avoir aujourd’hui une vision beaucoup plus intégrée des mécanismes fondamentaux de la biologie du développement. L’objectif de l’ouvrage est de fournir une vision synthétique et moderne de la discipline tout en montrant son lien avec la biologie cellulaire, la génétique, la physiologie et la médecine. Les principaux modèles, historiques ou émergents, sont présentés puis les grandes étapes du développement sont détaillées en s’appuyant sur les données les plus récentes. Un chapitre aborde l’importance de l’apport de la biologie du développement dans la compréhension de nombreuses pathologies, dont le cancer.}, keywords = {}, pubstate = {published}, tppubtype = {book} } La biologie du développement étudie les phénomènes qui permettent le passage d’un œuf à un organisme adulte. Cette discipline a beaucoup évolué ces dernières années avec l'essor des nouvelles techniques d’imagerie in vivo, des « omiques » et des techniques de transgénèse. Aux progrès technologiques s’ajoutent les avancées importantes en génétique et épigénétique, tout cela permettant d’avoir aujourd’hui une vision beaucoup plus intégrée des mécanismes fondamentaux de la biologie du développement. L’objectif de l’ouvrage est de fournir une vision synthétique et moderne de la discipline tout en montrant son lien avec la biologie cellulaire, la génétique, la physiologie et la médecine. Les principaux modèles, historiques ou émergents, sont présentés puis les grandes étapes du développement sont détaillées en s’appuyant sur les données les plus récentes. Un chapitre aborde l’importance de l’apport de la biologie du développement dans la compréhension de nombreuses pathologies, dont le cancer. |
| 17. | Lamiable, Olivier; Kellenberger, Christine; Kemp, Cordula; Troxler, Laurent; Pelte, Nadège; Boutros, Michael; Marques, Joao Trindade; Daeffler, Laurent; Hoffmann, Jules A; Roussel, Alain; Imler, Jean-Luc: Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila. PNAS, 113 (3), p. 698–703, 2016, ISSN: 0027-8424, 1091-6490. (type: Article de journal | Résumé | Liens | BibTeX) @article{lamiable_cytokine_2016, title = {Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila}, author = { Olivier Lamiable and Christine Kellenberger and Cordula Kemp and Laurent Troxler and Nadège Pelte and Michael Boutros and Joao Trindade Marques and Laurent Daeffler and Jules A. Hoffmann and Alain Roussel and Jean-Luc Imler}, url = {http://www.pnas.org/content/113/3/698.abstract}, doi = {10.1073/pnas.1516122113}, issn = {0027-8424, 1091-6490}, year = {2016}, date = {2016-01-19}, urldate = {2016-01-07}, journal = {PNAS}, volume = {113}, number = {3}, pages = {698–703}, abstract = {Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKγ or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-κB signaling and promote fly survival during the antiviral response.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKγ or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-κB signaling and promote fly survival during the antiviral response. |
| 18. | Baron, Olga Lucia; Deleury, Emeline; Reichhart, Jean-Marc; Coustau, Christine: The LBP/BPI multigenic family in invertebrates: Evolutionary history and evidences of specialization in mollusks. Developmental & Comparative Immunology, 57 , p. 20–30, 2016, ISSN: 0145305X. (type: Article de journal | Liens | BibTeX) @article{baron_lbp/bpi_2016, title = {The LBP/BPI multigenic family in invertebrates: Evolutionary history and evidences of specialization in mollusks}, author = { Olga Lucia Baron and Emeline Deleury and Jean-Marc Reichhart and Christine Coustau}, url = {http://linkinghub.elsevier.com/retrieve/pii/S0145305X15300756}, doi = {10.1016/j.dci.2015.11.006}, issn = {0145305X}, year = {2016}, date = {2016-01-01}, urldate = {2017-07-12}, journal = {Developmental & Comparative Immunology}, volume = {57}, pages = {20--30}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 19. | Lamiable, Olivier; Meignin, Carine; Imler, Jean-Luc: WntD and Diedel: Two immunomodulatory cytokines in Drosophila immunity. Fly (Austin), 10 (4), p. 187–194, 2016, ISSN: 1933-6942. (type: Article de journal | Résumé | Liens | BibTeX) @article{lamiable_wntd_2016, title = {WntD and Diedel: Two immunomodulatory cytokines in Drosophila immunity}, author = { Olivier Lamiable and Carine Meignin and Jean-Luc Imler}, url = {http://www.tandfonline.com/doi/abs/10.1080/19336934.2016.1202387?journalCode=kfly20}, doi = {10.1080/19336934.2016.1202387}, issn = {1933-6942}, year = {2016}, date = {2016-01-01}, journal = {Fly (Austin)}, volume = {10}, number = {4}, pages = {187--194}, abstract = {Remarkable progress has been made on the understanding of the basic mechanisms of innate immunity in flies, from sensing infection to production of effector molecules. However, how the immune response is orchestrated at the level of the organism remains poorly understood. While cytokines activating immune responses, such as Spaetzle or Unpaired-3, have been identified and characterized in Drosophila, much less is known regarding immunosuppressor cytokines. In a recent publication, we reported the identification of a novel cytokine, Diedel, which acts as systemic negative regulator of the IMD pathway. Here, we discuss the similarities between Diedel and WntD, another immunomodulatory cytokine and present evidence that the 2 molecules act independently from one another.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Remarkable progress has been made on the understanding of the basic mechanisms of innate immunity in flies, from sensing infection to production of effector molecules. However, how the immune response is orchestrated at the level of the organism remains poorly understood. While cytokines activating immune responses, such as Spaetzle or Unpaired-3, have been identified and characterized in Drosophila, much less is known regarding immunosuppressor cytokines. In a recent publication, we reported the identification of a novel cytokine, Diedel, which acts as systemic negative regulator of the IMD pathway. Here, we discuss the similarities between Diedel and WntD, another immunomodulatory cytokine and present evidence that the 2 molecules act independently from one another. |
| 20. | Martins, Nelson; Imler, Jean-Luc; Meignin, Carine: Discovery of novel targets for antivirals: learning from flies. Curr Opin Virol, 20 , p. 64–70, 2016, ISSN: 1879-6265. (type: Article de journal | Résumé | Liens | BibTeX) @article{martins_discovery_2016, title = {Discovery of novel targets for antivirals: learning from flies}, author = { Nelson Martins and Jean-Luc Imler and Carine Meignin}, url = {http://www.sciencedirect.com/science/article/pii/S1879625716301274}, doi = {10.1016/j.coviro.2016.09.005}, issn = {1879-6265}, year = {2016}, date = {2016-01-01}, journal = {Curr Opin Virol}, volume = {20}, pages = {64--70}, abstract = {Developing antiviral drugs is challenging due to the small number of targets in viruses, and the rapid evolution of viral genes. Animals have evolved a number of efficient antiviral defence mechanisms, which can serve as a source of inspiration for novel therapies. The genetically tractable insect Drosophila belongs to the most diverse group of animals. Genetic and transcriptomic analyses have recently identified Drosophila genes encoding viral restriction factors. Some of them represent evolutionary novelties and their characterization may provide hints for the design of directly acting antivirals. In addition, functional screens revealed conserved host factors required for efficient viral translation, such as the ribosomal protein RACK1 and the release factor Pelo. These proteins are promising candidates for host-targeted antivirals.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Developing antiviral drugs is challenging due to the small number of targets in viruses, and the rapid evolution of viral genes. Animals have evolved a number of efficient antiviral defence mechanisms, which can serve as a source of inspiration for novel therapies. The genetically tractable insect Drosophila belongs to the most diverse group of animals. Genetic and transcriptomic analyses have recently identified Drosophila genes encoding viral restriction factors. Some of them represent evolutionary novelties and their characterization may provide hints for the design of directly acting antivirals. In addition, functional screens revealed conserved host factors required for efficient viral translation, such as the ribosomal protein RACK1 and the release factor Pelo. These proteins are promising candidates for host-targeted antivirals. |
2018 |
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Articles de journaux |
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| 182. | Goto, Akira; Okado, Kiyoshi; Martins, Nelson; Cai, Hua; Barbier, Vincent; Lamiable, Olivier; Troxler, Laurent; Santiago, Estelle; Kuhn, Lauriane; Paik, Donggi; Silverman, Neal; Holleufer, Andreas; Hartmann, Rune; Liu, Jiyong; Peng, Tao; Hoffmann, Jules A; Meignin, Carine; Daeffler, Laurent; Imler, Jean-Luc The Kinase IKKβ Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila Article de journal Immunity, (49), p. 225-234, 2018. @article{Goto2018, title = {The Kinase IKKβ Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila}, author = {Akira Goto and Kiyoshi Okado and Nelson Martins and Hua Cai and Vincent Barbier and Olivier Lamiable and Laurent Troxler and Estelle Santiago and Lauriane Kuhn and Donggi Paik and Neal Silverman and Andreas Holleufer and Rune Hartmann and Jiyong Liu and Tao Peng and Jules A. Hoffmann and Carine Meignin and Laurent Daeffler and Jean-Luc Imler}, editor = {Elsevier Inc.}, url = {https://doi.org/10.1016/j.immuni.2018.07.013}, doi = {j.immuni.2018.07.013}, year = {2018}, date = {2018-08-21}, journal = {Immunity}, number = {49}, pages = {225-234}, abstract = {Antiviral immunity in Drosophila involves RNA interference and poorly characterized inducible responses. Here, we showed that two components of the IMD pathway, the kinase dIKKβ and the transcription factor Relish, were required to control infection by two picorna-like viruses. We identified a set of genes induced by viral infection and regulated by dIKKβ and Relish, which included an ortholog of STING. We showed that dSTING participated in the control of infection by picorna-like viruses, acting upstream of dIKKβ to regulate expression of Nazo, an antiviral factor. Our data reveal an antiviral function for STING in an animal model devoid of interferons and suggest an evolutionarily ancient role for this molecule in antiviral immunity.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Antiviral immunity in Drosophila involves RNA interference and poorly characterized inducible responses. Here, we showed that two components of the IMD pathway, the kinase dIKKβ and the transcription factor Relish, were required to control infection by two picorna-like viruses. We identified a set of genes induced by viral infection and regulated by dIKKβ and Relish, which included an ortholog of STING. We showed that dSTING participated in the control of infection by picorna-like viruses, acting upstream of dIKKβ to regulate expression of Nazo, an antiviral factor. Our data reveal an antiviral function for STING in an animal model devoid of interferons and suggest an evolutionarily ancient role for this molecule in antiviral immunity. |
2016 |
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Articles de journaux |
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| 181. | Lamiable, Olivier; Kellenberger, Christine; Kemp, Cordula; Troxler, Laurent; Pelte, Nadège; Boutros, Michael; Marques, Joao Trindade; Daeffler, Laurent; Hoffmann, Jules A; Roussel, Alain; Imler, Jean-Luc Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila Article de journal PNAS, 113 (3), p. 698–703, 2016, ISSN: 0027-8424, 1091-6490. @article{lamiable_cytokine_2016, title = {Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila}, author = { Olivier Lamiable and Christine Kellenberger and Cordula Kemp and Laurent Troxler and Nadège Pelte and Michael Boutros and Joao Trindade Marques and Laurent Daeffler and Jules A. Hoffmann and Alain Roussel and Jean-Luc Imler}, url = {http://www.pnas.org/content/113/3/698.abstract}, doi = {10.1073/pnas.1516122113}, issn = {0027-8424, 1091-6490}, year = {2016}, date = {2016-01-19}, urldate = {2016-01-07}, journal = {PNAS}, volume = {113}, number = {3}, pages = {698–703}, abstract = {Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKγ or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-κB signaling and promote fly survival during the antiviral response.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKγ or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-κB signaling and promote fly survival during the antiviral response. |
| 180. | Lamiable, Olivier; Arnold, Johan; da de Faria, Isaque Joao Silva; Olmo, Roenick Proveti; Bergami, Francesco; Meignin, Carine; Hoffmann, Jules A; Marques, Joao Trindade; Imler, Jean-Luc Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity Article de journal J. Virol., 90 (11), p. 5415–5426, 2016, ISSN: 0022-538X, 1098-5514. @article{lamiable_analysis_2016, title = {Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity}, author = { Olivier Lamiable and Johan Arnold and Isaque Joao da Silva de Faria and Roenick Proveti Olmo and Francesco Bergami and Carine Meignin and Jules A. Hoffmann and Joao Trindade Marques and Jean-Luc Imler}, url = {http://jvi.asm.org/content/90/11/5415}, doi = {10.1128/JVI.00238-16}, issn = {0022-538X, 1098-5514}, year = {2016}, date = {2016-01-01}, urldate = {2016-06-05}, journal = {J. Virol.}, volume = {90}, number = {11}, pages = {5415--5426}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
2014 |
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Articles de journaux |
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| 179. | Chtarbanova, Stanislava; Lamiable, Olivier; Lee, Kwang-Zin; Galiana, Delphine; Troxler, Laurent; Meignin, Carine; Hetru, Charles; Hoffmann, Jules A; Daeffler, Laurent; Imler, Jean-Luc Drosophila C virus systemic infection leads to intestinal obstruction Article de journal Journal of Virology, 88 (24), p. 14057–14069, 2014, ISSN: 1098-5514. @article{chtarbanova_drosophila_2014, title = {Drosophila C virus systemic infection leads to intestinal obstruction}, author = { Stanislava Chtarbanova and Olivier Lamiable and Kwang-Zin Lee and Delphine Galiana and Laurent Troxler and Carine Meignin and Charles Hetru and Jules A. Hoffmann and Laurent Daeffler and Jean-Luc Imler}, url = {http://jvi.asm.org/content/88/24/14057}, doi = {10.1128/JVI.02320-14}, issn = {1098-5514}, year = {2014}, date = {2014-12-01}, journal = {Journal of Virology}, volume = {88}, number = {24}, pages = {14057--14069}, abstract = {Drosophila C virus (DCV) is a positive-sense RNA virus belonging to the Dicistroviridae family. This natural pathogen of the model organism Drosophila melanogaster is commonly used to investigate antiviral host defense in flies, which involves both RNA interference and inducible responses. Although lethality is used routinely as a readout for the efficiency of the antiviral immune response in these studies, virus-induced pathologies in flies still are poorly understood. Here, we characterize the pathogenesis associated with systemic DCV infection. Comparison of the transcriptome of flies infected with DCV or two other positive-sense RNA viruses, Flock House virus and Sindbis virus, reveals that DCV infection, unlike those of the other two viruses, represses the expression of a large number of genes. Several of these genes are expressed specifically in the midgut and also are repressed by starvation. We show that systemic DCV infection triggers a nutritional stress in Drosophila which results from intestinal obstruction with the accumulation of peritrophic matrix at the entry of the midgut and the accumulation of the food ingested in the crop, a blind muscular food storage organ. The related virus cricket paralysis virus (CrPV), which efficiently grows in Drosophila, does not trigger this pathology. We show that DCV, but not CrPV, infects the smooth muscles surrounding the crop, causing extensive cytopathology and strongly reducing the rate of contractions. We conclude that the pathogenesis associated with systemic DCV infection results from the tropism of the virus for an important organ within the foregut of dipteran insects, the crop. IMPORTANCE: DCV is one of the few identified natural viral pathogens affecting the model organism Drosophila melanogaster. As such, it is an important virus for the deciphering of host-virus interactions in insects. We characterize here the pathogenesis associated with DCV infection in flies and show that it results from the tropism of the virus for an essential but poorly characterized organ in the digestive tract, the crop. Our results may have relevance for other members of the Dicistroviridae, some of which are pathogenic to beneficial or pest insect species.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Drosophila C virus (DCV) is a positive-sense RNA virus belonging to the Dicistroviridae family. This natural pathogen of the model organism Drosophila melanogaster is commonly used to investigate antiviral host defense in flies, which involves both RNA interference and inducible responses. Although lethality is used routinely as a readout for the efficiency of the antiviral immune response in these studies, virus-induced pathologies in flies still are poorly understood. Here, we characterize the pathogenesis associated with systemic DCV infection. Comparison of the transcriptome of flies infected with DCV or two other positive-sense RNA viruses, Flock House virus and Sindbis virus, reveals that DCV infection, unlike those of the other two viruses, represses the expression of a large number of genes. Several of these genes are expressed specifically in the midgut and also are repressed by starvation. We show that systemic DCV infection triggers a nutritional stress in Drosophila which results from intestinal obstruction with the accumulation of peritrophic matrix at the entry of the midgut and the accumulation of the food ingested in the crop, a blind muscular food storage organ. The related virus cricket paralysis virus (CrPV), which efficiently grows in Drosophila, does not trigger this pathology. We show that DCV, but not CrPV, infects the smooth muscles surrounding the crop, causing extensive cytopathology and strongly reducing the rate of contractions. We conclude that the pathogenesis associated with systemic DCV infection results from the tropism of the virus for an important organ within the foregut of dipteran insects, the crop. IMPORTANCE: DCV is one of the few identified natural viral pathogens affecting the model organism Drosophila melanogaster. As such, it is an important virus for the deciphering of host-virus interactions in insects. We characterize here the pathogenesis associated with DCV infection in flies and show that it results from the tropism of the virus for an essential but poorly characterized organ in the digestive tract, the crop. Our results may have relevance for other members of the Dicistroviridae, some of which are pathogenic to beneficial or pest insect species. |
| 178. | Majzoub, Karim; Hafirassou, Mohamed Lamine ; Meignin, Carine ; Goto, Akira ; Marzi, Stefano ; Fedorova, Antonina ; Verdier, Yann ; Vinh, Joëlle ; Hoffmann, Jules A; Martin, Franck ; Baumert, Thomas F; Schuster, Catherine ; Imler, Jean-Luc RACK1 controls IRES-mediated translation of viruses Article de journal Cell, 159 (5), p. 1086–1095, 2014, ISSN: 1097-4172. @article{majzoub_rack1_2014, title = {RACK1 controls IRES-mediated translation of viruses}, author = { Karim Majzoub and Mohamed Lamine Hafirassou and Carine Meignin and Akira Goto and Stefano Marzi and Antonina Fedorova and Yann Verdier and Joëlle Vinh and Jules A. Hoffmann and Franck Martin and Thomas F. Baumert and Catherine Schuster and Jean-Luc Imler}, doi = {10.1016/j.cell.2014.10.041}, issn = {1097-4172}, year = {2014}, date = {2014-11-01}, journal = {Cell}, volume = {159}, number = {5}, pages = {1086--1095}, abstract = {Fighting viral infections is hampered by the scarcity of viral targets and their variability, resulting in development of resistance. Viruses depend on cellular molecules-which are attractive alternative targets-for their life cycle, provided that they are dispensable for normal cell functions. Using the model organism Drosophila melanogaster, we identify the ribosomal protein RACK1 as a cellular factor required for infection by internal ribosome entry site (IRES)-containing viruses. We further show that RACK1 is an essential determinant for hepatitis C virus translation and infection, indicating that its function is conserved for distantly related human and fly viruses. Inhibition of RACK1 does not affect Drosophila or human cell viability and proliferation, and RACK1-silenced adult flies are viable, indicating that this protein is not essential for general translation. Our findings demonstrate a specific function for RACK1 in selective mRNA translation and uncover a target for the development of broad antiviral intervention.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Fighting viral infections is hampered by the scarcity of viral targets and their variability, resulting in development of resistance. Viruses depend on cellular molecules-which are attractive alternative targets-for their life cycle, provided that they are dispensable for normal cell functions. Using the model organism Drosophila melanogaster, we identify the ribosomal protein RACK1 as a cellular factor required for infection by internal ribosome entry site (IRES)-containing viruses. We further show that RACK1 is an essential determinant for hepatitis C virus translation and infection, indicating that its function is conserved for distantly related human and fly viruses. Inhibition of RACK1 does not affect Drosophila or human cell viability and proliferation, and RACK1-silenced adult flies are viable, indicating that this protein is not essential for general translation. Our findings demonstrate a specific function for RACK1 in selective mRNA translation and uncover a target for the development of broad antiviral intervention. |
| 177. | Tartey, Sarang; Matsushita, Kazufumi ; Vandenbon, Alexis ; Ori, Daisuke ; Imamura, Tomoko ; Mino, Takashi ; Standley, Daron M; Hoffmann, Jules A; Reichhart, Jean-Marc ; Akira, Shizuo ; Takeuchi, Osamu Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex Article de journal EMBO J., 33 (20), p. 2332–2348, 2014, ISSN: 1460-2075. @article{tartey_akirin2_2014, title = {Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex}, author = { Sarang Tartey and Kazufumi Matsushita and Alexis Vandenbon and Daisuke Ori and Tomoko Imamura and Takashi Mino and Daron M. Standley and Jules A. Hoffmann and Jean-Marc Reichhart and Shizuo Akira and Osamu Takeuchi}, doi = {10.15252/embj.201488447}, issn = {1460-2075}, year = {2014}, date = {2014-10-01}, journal = {EMBO J.}, volume = {33}, number = {20}, pages = {2332--2348}, abstract = {Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection. |
| 176. | Goto, Akira; Fukuyama, Hidehiro ; Imler, Jean-Luc ; Hoffmann, Jules A The chromatin regulator DMAP1 modulates activity of the nuclear factor B (NF-B) transcription factor Relish in the Drosophila innate immune response Article de journal The Journal of Biological Chemistry, 289 (30), p. 20470–20476, 2014, ISSN: 1083-351X. @article{goto_chromatin_2014, title = {The chromatin regulator DMAP1 modulates activity of the nuclear factor B (NF-B) transcription factor Relish in the Drosophila innate immune response}, author = { Akira Goto and Hidehiro Fukuyama and Jean-Luc Imler and Jules A. Hoffmann}, doi = {10.1074/jbc.C114.553719}, issn = {1083-351X}, year = {2014}, date = {2014-07-01}, journal = {The Journal of Biological Chemistry}, volume = {289}, number = {30}, pages = {20470--20476}, abstract = {The host defense of the model organism Drosophila is under the control of two major signaling cascades controlling transcription factors of the NF-B family, the Toll and the immune deficiency (IMD) pathways. The latter shares extensive similarities with the mammalian TNF-R pathway and was initially discovered for its role in anti-Gram-negative bacterial reactions. A previous interactome study from this laboratory reported that an unexpectedly large number of proteins are binding to the canonical components of the IMD pathway. Here, we focus on DNA methyltransferase-associated protein 1 (DMAP1), which this study identified as an interactant of Relish, a Drosophila transcription factor reminiscent of the mammalian p105 NF-B protein. We show that silencing of DMAP1 expression both in S2 cells and in flies results in a significant reduction of Escherichia coli-induced expression of antimicrobial peptides. Epistatic analysis indicates that DMAP1 acts in parallel or downstream of Relish. Co-immunoprecipitation experiments further reveal that, in addition to Relish, DMAP1 also interacts with Akirin and the Brahma-associated protein 55 kDa (BAP55). Taken together, these results reveal that DMAP1 is a novel nuclear modulator of the IMD pathway, possibly acting at the level of chromatin remodeling.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The host defense of the model organism Drosophila is under the control of two major signaling cascades controlling transcription factors of the NF-B family, the Toll and the immune deficiency (IMD) pathways. The latter shares extensive similarities with the mammalian TNF-R pathway and was initially discovered for its role in anti-Gram-negative bacterial reactions. A previous interactome study from this laboratory reported that an unexpectedly large number of proteins are binding to the canonical components of the IMD pathway. Here, we focus on DNA methyltransferase-associated protein 1 (DMAP1), which this study identified as an interactant of Relish, a Drosophila transcription factor reminiscent of the mammalian p105 NF-B protein. We show that silencing of DMAP1 expression both in S2 cells and in flies results in a significant reduction of Escherichia coli-induced expression of antimicrobial peptides. Epistatic analysis indicates that DMAP1 acts in parallel or downstream of Relish. Co-immunoprecipitation experiments further reveal that, in addition to Relish, DMAP1 also interacts with Akirin and the Brahma-associated protein 55 kDa (BAP55). Taken together, these results reveal that DMAP1 is a novel nuclear modulator of the IMD pathway, possibly acting at the level of chromatin remodeling. |
Book Chapters |
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| 175. | Imler, Jean-Luc; Hoffmann, Jules A Le défi des maladies infectieuses Book Chapter Ph. Cramer collection Guérir et prévenir demain, (Ed.): Chapitre « L’immunité innée », p. 167-174, Editions DOCIS, 2014, ISBN: 978-2-85525-390-9. @inbook{Imler2014, title = {Le défi des maladies infectieuses}, author = {Jean-Luc Imler and Jules A. Hoffmann}, editor = {Ph. Cramer, collection Guérir et prévenir demain,}, isbn = {978-2-85525-390-9}, year = {2014}, date = {2014-06-01}, pages = {167-174}, publisher = {Editions DOCIS}, chapter = {« L’immunité innée »}, abstract = {La lèpre fait des ravages dès l’Antiquité, les épidémies de peste tuent au Moyen Âge et celles de choléra dévastent l’Inde. La tuberculose émerge véritablement au XIXème siècle, la grippe espagnole a fait vingt millions de morts en 1918 et de nouvelles maladies apparaissent : les infections hospitalières, les hépatites, le SIDA, les fièvres hémorragiques, la légionellose,… Toutes ces maladies ont un point commun, ce sont des maladies infectieuses qui sont pour la médecine un vrai défi, tant elles sont dévastatrices. L’innovation a eu et continue à avoir un rôle essentiel dans la caractérisation de ces maladies, la découverte de l’agent responsable, leur traitement et leur prévention. Ce livre, dont les auteurs font partie des plus éminents spécialistes français et européens des maladies infectieuses décrit, de façon abordable par tous, aussi bien les découvertes et les inventions essentielles à ce domaine que les avancées médicales.}, keywords = {}, pubstate = {published}, tppubtype = {inbook} } La lèpre fait des ravages dès l’Antiquité, les épidémies de peste tuent au Moyen Âge et celles de choléra dévastent l’Inde. La tuberculose émerge véritablement au XIXème siècle, la grippe espagnole a fait vingt millions de morts en 1918 et de nouvelles maladies apparaissent : les infections hospitalières, les hépatites, le SIDA, les fièvres hémorragiques, la légionellose,… Toutes ces maladies ont un point commun, ce sont des maladies infectieuses qui sont pour la médecine un vrai défi, tant elles sont dévastatrices. L’innovation a eu et continue à avoir un rôle essentiel dans la caractérisation de ces maladies, la découverte de l’agent responsable, leur traitement et leur prévention. Ce livre, dont les auteurs font partie des plus éminents spécialistes français et européens des maladies infectieuses décrit, de façon abordable par tous, aussi bien les découvertes et les inventions essentielles à ce domaine que les avancées médicales. |
2013 |
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Articles de journaux |
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| 174. | Fukuyama, Hidehiro; Verdier, Yann; Guan, Yongsheng; Makino-Okamura, Chieko; Shilova, Victoria; Liu, Xi; Maksoud, Elie; Matsubayashi, Jun; Haddad, Iman; Spirohn, Kerstin; Ono, Kenichiro; Hetru, Charles; Rossier, Jean; Ideker, Trey; Boutros, Michael; Vinh, Joëlle; Hoffmann, Jules A Landscape of protein-protein interactions in Drosophila immune deficiency signaling during bacterial challenge Article de journal Proc. Natl. Acad. Sci. U.S.A., 110 (26), p. 10717–10722, 2013, ISSN: 1091-6490. @article{fukuyama_landscape_2013, title = {Landscape of protein-protein interactions in Drosophila immune deficiency signaling during bacterial challenge}, author = { Hidehiro Fukuyama and Yann Verdier and Yongsheng Guan and Chieko Makino-Okamura and Victoria Shilova and Xi Liu and Elie Maksoud and Jun Matsubayashi and Iman Haddad and Kerstin Spirohn and Kenichiro Ono and Charles Hetru and Jean Rossier and Trey Ideker and Michael Boutros and Joëlle Vinh and Jules A. Hoffmann}, doi = {10.1073/pnas.1304380110}, issn = {1091-6490}, year = {2013}, date = {2013-06-01}, journal = {Proc. Natl. Acad. Sci. U.S.A.}, volume = {110}, number = {26}, pages = {10717--10722}, abstract = {The Drosophila defense against pathogens largely relies on the activation of two signaling pathways: immune deficiency (IMD) and Toll. The IMD pathway is triggered mainly by Gram-negative bacteria, whereas the Toll pathway responds predominantly to Gram-positive bacteria and fungi. The activation of these pathways leads to the rapid induction of numerous NF-κB-induced immune response genes, including antimicrobial peptide genes. The IMD pathway shows significant similarities with the TNF receptor pathway. Recent evidence indicates that the IMD pathway is also activated in response to various noninfectious stimuli (i.e., inflammatory-like reactions). To gain a better understanding of the molecular machinery underlying the pleiotropic functions of this pathway, we first performed a comprehensive proteomics analysis to identify the proteins interacting with the 11 canonical members of the pathway initially identified by genetic studies. We identified 369 interacting proteins (corresponding to 291 genes) in heat-killed Escherichia coli-stimulated Drosophila S2 cells, 92% of which have human orthologs. A comparative analysis of gene ontology from fly or human gene annotation databases points to four significant common categories: (i) the NuA4, nucleosome acetyltransferase of H4, histone acetyltransferase complex, (ii) the switching defective/sucrose nonfermenting-type chromatin remodeling complex, (iii) transcription coactivator activity, and (iv) translation factor activity. Here we demonstrate that sumoylation of the IκB kinase homolog immune response-deficient 5 plays an important role in the induction of antimicrobial peptide genes through a highly conserved sumoylation consensus site during bacterial challenge. Taken together, the proteomics data presented here provide a unique avenue for a comparative functional analysis of proteins involved in innate immune reactions in flies and mammals.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Drosophila defense against pathogens largely relies on the activation of two signaling pathways: immune deficiency (IMD) and Toll. The IMD pathway is triggered mainly by Gram-negative bacteria, whereas the Toll pathway responds predominantly to Gram-positive bacteria and fungi. The activation of these pathways leads to the rapid induction of numerous NF-κB-induced immune response genes, including antimicrobial peptide genes. The IMD pathway shows significant similarities with the TNF receptor pathway. Recent evidence indicates that the IMD pathway is also activated in response to various noninfectious stimuli (i.e., inflammatory-like reactions). To gain a better understanding of the molecular machinery underlying the pleiotropic functions of this pathway, we first performed a comprehensive proteomics analysis to identify the proteins interacting with the 11 canonical members of the pathway initially identified by genetic studies. We identified 369 interacting proteins (corresponding to 291 genes) in heat-killed Escherichia coli-stimulated Drosophila S2 cells, 92% of which have human orthologs. A comparative analysis of gene ontology from fly or human gene annotation databases points to four significant common categories: (i) the NuA4, nucleosome acetyltransferase of H4, histone acetyltransferase complex, (ii) the switching defective/sucrose nonfermenting-type chromatin remodeling complex, (iii) transcription coactivator activity, and (iv) translation factor activity. Here we demonstrate that sumoylation of the IκB kinase homolog immune response-deficient 5 plays an important role in the induction of antimicrobial peptide genes through a highly conserved sumoylation consensus site during bacterial challenge. Taken together, the proteomics data presented here provide a unique avenue for a comparative functional analysis of proteins involved in innate immune reactions in flies and mammals. |
| 173. | Bonnay, François; Cohen-Berros, Eva ; Hoffmann, Martine ; Kim, Sabrina Y; Boulianne, Gabrielle L; Hoffmann, Jules A; Matt, Nicolas ; Reichhart, Jean-Marc Big bang gene modulates gut immune tolerance in Drosophila Article de journal Proc. Natl. Acad. Sci. U.S.A., 110 (8), p. 2957–2962, 2013, ISSN: 1091-6490. @article{bonnay_big_2013, title = {Big bang gene modulates gut immune tolerance in Drosophila}, author = { François Bonnay and Eva Cohen-Berros and Martine Hoffmann and Sabrina Y. Kim and Gabrielle L. Boulianne and Jules A. Hoffmann and Nicolas Matt and Jean-Marc Reichhart}, doi = {10.1073/pnas.1221910110}, issn = {1091-6490}, year = {2013}, date = {2013-02-01}, journal = {Proc. Natl. Acad. Sci. U.S.A.}, volume = {110}, number = {8}, pages = {2957--2962}, abstract = {Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases. |
| 172. | Kemp, Cordula; Mueller, Stefanie ; Goto, Akira ; Barbier, Vincent ; Paro, Simona ; Bonnay, François ; Dostert, Catherine ; Troxler, Laurent ; Hetru, Charles ; Meignin, Carine ; Pfeffer, Sébastien ; Hoffmann, Jules A; Imler, Jean-Luc Broad RNA interference-mediated antiviral immunity and virus-specific inducible responses in Drosophila Article de journal Journal of Immunology (Baltimore, Md.: 1950), 190 (2), p. 650–658, 2013, ISSN: 1550-6606. @article{kemp_broad_2013, title = {Broad RNA interference-mediated antiviral immunity and virus-specific inducible responses in Drosophila}, author = { Cordula Kemp and Stefanie Mueller and Akira Goto and Vincent Barbier and Simona Paro and François Bonnay and Catherine Dostert and Laurent Troxler and Charles Hetru and Carine Meignin and Sébastien Pfeffer and Jules A. Hoffmann and Jean-Luc Imler}, doi = {10.4049/jimmunol.1102486}, issn = {1550-6606}, year = {2013}, date = {2013-01-01}, journal = {Journal of Immunology (Baltimore, Md.: 1950)}, volume = {190}, number = {2}, pages = {650--658}, abstract = {The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. The response of Drosophila to virus infections remains poorly characterized and appears to involve two facets. On the one hand, RNA interference involves the recognition and processing of dsRNA into small interfering RNAs by the host RNase Dicer-2 (Dcr-2), whereas, on the other hand, an inducible response controlled by the evolutionarily conserved JAK-STAT pathway contributes to the antiviral host defense. To clarify the contribution of the small interfering RNA and JAK-STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type and mutant for Dcr-2 or the JAK kinase Hopscotch to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by Drosophila C virus and cricket paralysis virus, two members of the Dicistroviridae family, which contrasts with the susceptibility of Dcr-2 mutant flies to many viruses, including the DNA virus invertebrate iridescent virus 6. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by Drosophila C virus or by two unrelated RNA viruses, Flock House virus and Sindbis virus. Overall, our data reveal that RNA interference is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK-STAT pathway appears to be virus specific.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. The response of Drosophila to virus infections remains poorly characterized and appears to involve two facets. On the one hand, RNA interference involves the recognition and processing of dsRNA into small interfering RNAs by the host RNase Dicer-2 (Dcr-2), whereas, on the other hand, an inducible response controlled by the evolutionarily conserved JAK-STAT pathway contributes to the antiviral host defense. To clarify the contribution of the small interfering RNA and JAK-STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type and mutant for Dcr-2 or the JAK kinase Hopscotch to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by Drosophila C virus and cricket paralysis virus, two members of the Dicistroviridae family, which contrasts with the susceptibility of Dcr-2 mutant flies to many viruses, including the DNA virus invertebrate iridescent virus 6. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by Drosophila C virus or by two unrelated RNA viruses, Flock House virus and Sindbis virus. Overall, our data reveal that RNA interference is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK-STAT pathway appears to be virus specific. |
2012 |
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Articles de journaux |
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| 171. | Lemaitre, Bruno; Nicolas, Emmanuelle ; Michaut, Lydia ; Reichhart, Jean-Marc ; Hoffmann, Jules A Pillars article: the dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996. 86: 973-983 Article de journal J. Immunol., 188 (11), p. 5210–5220, 2012, ISSN: 1550-6606. @article{lemaitre_pillars_2012, title = {Pillars article: the dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996. 86: 973-983}, author = { Bruno Lemaitre and Emmanuelle Nicolas and Lydia Michaut and Jean-Marc Reichhart and Jules A. Hoffmann}, issn = {1550-6606}, year = {2012}, date = {2012-06-01}, journal = {J. Immunol.}, volume = {188}, number = {11}, pages = {5210--5220}, abstract = {The cytokine-induced activation cascade of NF-kappaB in mammals and the activation of the morphogen dorsal in Drosophila embryos show striking structural and functional similarities (Toll/IL-1, Cactus/I-kappaB, and dorsal/NF-kappaB). Here we demonstrate that these parallels extend to the immune response of Drosophila. In particular, the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spätzle regulatory gene cassette, control expression of the antifungal peptide gene drosomycin in adults. We also show that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection. Antibacterial genes are induced either by a distinct pathway involving the immune deficiency gene (imd) or by combined activation of both imd and dorsoventral pathways.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The cytokine-induced activation cascade of NF-kappaB in mammals and the activation of the morphogen dorsal in Drosophila embryos show striking structural and functional similarities (Toll/IL-1, Cactus/I-kappaB, and dorsal/NF-kappaB). Here we demonstrate that these parallels extend to the immune response of Drosophila. In particular, the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spätzle regulatory gene cassette, control expression of the antifungal peptide gene drosomycin in adults. We also show that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection. Antibacterial genes are induced either by a distinct pathway involving the immune deficiency gene (imd) or by combined activation of both imd and dorsoventral pathways. |
| 170. | Liu, Xi; Sano, Teruyuki; Guan, Yongsheng; Nagata, Shigekazu; Hoffmann, Jules A; Fukuyama, Hidehiro Drosophila EYA regulates the immune response against DNA through an evolutionarily conserved threonine phosphatase motif Article de journal PLoS ONE, 7 (8), p. e42725, 2012, ISSN: 1932-6203. @article{liu_drosophila_2012, title = {Drosophila EYA regulates the immune response against DNA through an evolutionarily conserved threonine phosphatase motif}, author = { Xi Liu and Teruyuki Sano and Yongsheng Guan and Shigekazu Nagata and Jules A. Hoffmann and Hidehiro Fukuyama}, doi = {10.1371/journal.pone.0042725}, issn = {1932-6203}, year = {2012}, date = {2012-01-01}, journal = {PLoS ONE}, volume = {7}, number = {8}, pages = {e42725}, abstract = {Innate immune responses against DNA are essential to counter both pathogen infections and tissue damages. Mammalian EYAs were recently shown to play a role in regulating the innate immune responses against DNA. Here, we demonstrate that the unique Drosophila eya gene is also involved in the response specific to DNA. Haploinsufficiency of eya in mutants deficient for lysosomal DNase activity (DNaseII) reduces antimicrobial peptide gene expression, a hallmark for immune responses in flies. Like the mammalian orthologues, Drosophila EYA features a N-terminal threonine and C-terminal tyrosine phosphatase domain. Through the generation of a series of mutant EYA fly strains, we show that the threonine phosphatase domain, but not the tyrosine phosphatase domain, is responsible for the innate immune response against DNA. A similar role for the threonine phosphatase domain in mammalian EYA4 had been surmised on the basis of in vitro studies. Furthermore EYA associates with IKKβ and full-length RELISH, and the induction of the IMD pathway-dependent antimicrobial peptide gene is independent of SO. Our data provide the first in vivo demonstration for the immune function of EYA and point to their conserved immune function in response to endogenous DNA, throughout evolution.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Innate immune responses against DNA are essential to counter both pathogen infections and tissue damages. Mammalian EYAs were recently shown to play a role in regulating the innate immune responses against DNA. Here, we demonstrate that the unique Drosophila eya gene is also involved in the response specific to DNA. Haploinsufficiency of eya in mutants deficient for lysosomal DNase activity (DNaseII) reduces antimicrobial peptide gene expression, a hallmark for immune responses in flies. Like the mammalian orthologues, Drosophila EYA features a N-terminal threonine and C-terminal tyrosine phosphatase domain. Through the generation of a series of mutant EYA fly strains, we show that the threonine phosphatase domain, but not the tyrosine phosphatase domain, is responsible for the innate immune response against DNA. A similar role for the threonine phosphatase domain in mammalian EYA4 had been surmised on the basis of in vitro studies. Furthermore EYA associates with IKKβ and full-length RELISH, and the induction of the IMD pathway-dependent antimicrobial peptide gene is independent of SO. Our data provide the first in vivo demonstration for the immune function of EYA and point to their conserved immune function in response to endogenous DNA, throughout evolution. |
Book Chapters |
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| 169. | Imler, Jean-Luc; Hoffmann, Jules A Nucleic Acid Sensors and Antiviral Immunity Book Chapter eds T. Fujita & P. Sambhara, (Ed.): Chapitre 1 : Antiviral responses in invertebrates, p. 1-18, Landes Bioscience, 2012. @inbook{Imler2012, title = {Nucleic Acid Sensors and Antiviral Immunity}, author = {Jean-Luc Imler and Jules A. Hoffmann}, editor = {T. Fujita & P. Sambhara, eds}, year = {2012}, date = {2012-06-01}, pages = {1-18}, publisher = {Landes Bioscience}, chapter = {1 : Antiviral responses in invertebrates}, keywords = {}, pubstate = {published}, tppubtype = {inbook} } |
2011 |
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Articles de journaux |
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| 168. | Eleftherianos, Ioannis; Won, Sungyong ; Chtarbanova, Stanislava ; Squiban, Barbara ; Ocorr, Karen ; Bodmer, Rolf ; Beutler, Bruce ; Hoffmann, Jules A; Imler, Jean-Luc ATP-sensitive potassium channel (K(ATP))-dependent regulation of cardiotropic viral infections Article de journal Proceedings of the National Academy of Sciences of the United States of America, 108 (29), p. 12024–12029, 2011, ISSN: 1091-6490. @article{eleftherianos_atp-sensitive_2011, title = {ATP-sensitive potassium channel (K(ATP))-dependent regulation of cardiotropic viral infections}, author = { Ioannis Eleftherianos and Sungyong Won and Stanislava Chtarbanova and Barbara Squiban and Karen Ocorr and Rolf Bodmer and Bruce Beutler and Jules A. Hoffmann and Jean-Luc Imler}, doi = {10.1073/pnas.1108926108}, issn = {1091-6490}, year = {2011}, date = {2011-07-01}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {108}, number = {29}, pages = {12024--12029}, abstract = {The effects of the cellular environment on innate immunity remain poorly characterized. Here, we show that in Drosophila ATP-sensitive potassium channels (K(ATP)) mediate resistance to a cardiotropic RNA virus, Flock House virus (FHV). FHV viral load in the heart rapidly increases in K(ATP) mutant flies, leading to increased viremia and accelerated death. The effect of K(ATP) channels is dependent on the RNA interference genes Dcr-2, AGO2, and r2d2, indicating that an activity associated with this potassium channel participates in this antiviral pathway in Drosophila. Flies treated with the K(ATP) agonist drug pinacidil are protected against FHV infection, thus demonstrating the importance of this regulation of innate immunity by the cellular environment in the heart. In mice, the Coxsackievirus B3 replicates to higher titers in the hearts of mayday mutant animals, which are deficient in the Kir6.1 subunit of K(ATP) channels, than in controls. Together, our data suggest that K(ATP) channel deregulation can have a critical impact on innate antiviral immunity in the heart.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The effects of the cellular environment on innate immunity remain poorly characterized. Here, we show that in Drosophila ATP-sensitive potassium channels (K(ATP)) mediate resistance to a cardiotropic RNA virus, Flock House virus (FHV). FHV viral load in the heart rapidly increases in K(ATP) mutant flies, leading to increased viremia and accelerated death. The effect of K(ATP) channels is dependent on the RNA interference genes Dcr-2, AGO2, and r2d2, indicating that an activity associated with this potassium channel participates in this antiviral pathway in Drosophila. Flies treated with the K(ATP) agonist drug pinacidil are protected against FHV infection, thus demonstrating the importance of this regulation of innate immunity by the cellular environment in the heart. In mice, the Coxsackievirus B3 replicates to higher titers in the hearts of mayday mutant animals, which are deficient in the Kir6.1 subunit of K(ATP) channels, than in controls. Together, our data suggest that K(ATP) channel deregulation can have a critical impact on innate antiviral immunity in the heart. |
2010 |
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Articles de journaux |
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| 167. | Mueller, Stefanie; Gausson, Valérie ; Vodovar, Nicolas ; Deddouche, Safia ; Troxler, Laurent ; Perot, Jonathan ; Pfeffer, Sébastien ; Hoffmann, Jules A; Saleh, Maria-Carla ; Imler, Jean-Luc RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila Article de journal Proceedings of the National Academy of Sciences of the United States of America, 107 (45), p. 19390–19395, 2010, ISSN: 1091-6490. @article{mueller_rnai-mediated_2010, title = {RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila}, author = { Stefanie Mueller and Valérie Gausson and Nicolas Vodovar and Safia Deddouche and Laurent Troxler and Jonathan Perot and Sébastien Pfeffer and Jules A. Hoffmann and Maria-Carla Saleh and Jean-Luc Imler}, doi = {10.1073/pnas.1014378107}, issn = {1091-6490}, year = {2010}, date = {2010-11-01}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, number = {45}, pages = {19390--19395}, abstract = {Activation of innate antiviral responses in multicellular organisms relies on the recognition of structural differences between viral and cellular RNAs. Double-stranded (ds)RNA, produced during viral replication, is a well-known activator of antiviral defenses and triggers interferon production in vertebrates and RNAi in invertebrates and plants. Previous work in mammalian cells indicates that negative-strand RNA viruses do not appear to generate dsRNA, and that activation of innate immunity is triggered by the recognition of the uncapped 5' ends of viral RNA. This finding raises the question whether antiviral RNAi, which is triggered by the presence of dsRNA in insects, represents an effective host-defense mechanism against negative-strand RNA viruses. Here, we show that the negative-strand RNA virus vesicular stomatitis virus (VSV) does not produce easily detectable amounts of dsRNA in Drosophila cells. Nevertheless, RNAi represents a potent response to VSV infection, as illustrated by the high susceptibility of RNAi-defective mutant flies to this virus. VSV-derived small RNAs produced in infected cells or flies uniformly cover the viral genome, and equally map the genome and antigenome RNAs, indicating that they derive from dsRNA. Our findings reveal that RNAi is not restricted to the defense against positive-strand or dsRNA viruses but can also be highly efficient against a negative-strand RNA virus. This result is of particular interest in view of the frequent transmission of medically relevant negative-strand RNA viruses to humans by insect vectors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Activation of innate antiviral responses in multicellular organisms relies on the recognition of structural differences between viral and cellular RNAs. Double-stranded (ds)RNA, produced during viral replication, is a well-known activator of antiviral defenses and triggers interferon production in vertebrates and RNAi in invertebrates and plants. Previous work in mammalian cells indicates that negative-strand RNA viruses do not appear to generate dsRNA, and that activation of innate immunity is triggered by the recognition of the uncapped 5' ends of viral RNA. This finding raises the question whether antiviral RNAi, which is triggered by the presence of dsRNA in insects, represents an effective host-defense mechanism against negative-strand RNA viruses. Here, we show that the negative-strand RNA virus vesicular stomatitis virus (VSV) does not produce easily detectable amounts of dsRNA in Drosophila cells. Nevertheless, RNAi represents a potent response to VSV infection, as illustrated by the high susceptibility of RNAi-defective mutant flies to this virus. VSV-derived small RNAs produced in infected cells or flies uniformly cover the viral genome, and equally map the genome and antigenome RNAs, indicating that they derive from dsRNA. Our findings reveal that RNAi is not restricted to the defense against positive-strand or dsRNA viruses but can also be highly efficient against a negative-strand RNA virus. This result is of particular interest in view of the frequent transmission of medically relevant negative-strand RNA viruses to humans by insect vectors. |
2009 |
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Articles de journaux |
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| 166. | Hetru, Charles; Hoffmann, Jules A NF-kappaB in the immune response of Drosophila Article de journal Cold Spring Harb Perspect Biol, 1 (6), p. a000232, 2009, ISSN: 1943-0264. @article{hetru_nf-kappab_2009, title = {NF-kappaB in the immune response of Drosophila}, author = { Charles Hetru and Jules A. Hoffmann}, doi = {10.1101/cshperspect.a000232}, issn = {1943-0264}, year = {2009}, date = {2009-12-01}, journal = {Cold Spring Harb Perspect Biol}, volume = {1}, number = {6}, pages = {a000232}, abstract = {The nuclear factor kappaB (NF-kappaB) pathways play a major role in Drosophila host defense. Two recognition and signaling cascades control this immune response. The Toll pathway is activated by Gram-positive bacteria and by fungi, whereas the immune deficiency (Imd) pathway responds to Gram-negative bacterial infection. The basic mechanisms of recognition of these various types of microbial infections by the adult fly are now globally understood. Even though some elements are missing in the intracellular pathways, numerous proteins and interactions have been identified. In this article, we present a general picture of the immune functions of NF-kappaB in Drosophila with all the partners involved in recognition and in the signaling cascades.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The nuclear factor kappaB (NF-kappaB) pathways play a major role in Drosophila host defense. Two recognition and signaling cascades control this immune response. The Toll pathway is activated by Gram-positive bacteria and by fungi, whereas the immune deficiency (Imd) pathway responds to Gram-negative bacterial infection. The basic mechanisms of recognition of these various types of microbial infections by the adult fly are now globally understood. Even though some elements are missing in the intracellular pathways, numerous proteins and interactions have been identified. In this article, we present a general picture of the immune functions of NF-kappaB in Drosophila with all the partners involved in recognition and in the signaling cascades. |
| 165. | Mishima, Yumiko; Quintin, Jessica; Aimanianda, Vishukumar; Kellenberger, Christine; Coste, Franck; Clavaud, Cecile; Hetru, Charles; Hoffmann, Jules A; Latgé, Jean-Paul; Ferrandon, Dominique; Roussel, Alain The N-terminal domain of Drosophila Gram-negative binding protein 3 (GNBP3) defines a novel family of fungal pattern recognition receptors Article de journal J. Biol. Chem., 284 (42), p. 28687–28697, 2009, ISSN: 1083-351X. @article{mishima_n-terminal_2009, title = {The N-terminal domain of Drosophila Gram-negative binding protein 3 (GNBP3) defines a novel family of fungal pattern recognition receptors}, author = { Yumiko Mishima and Jessica Quintin and Vishukumar Aimanianda and Christine Kellenberger and Franck Coste and Cecile Clavaud and Charles Hetru and Jules A. Hoffmann and Jean-Paul Latgé and Dominique Ferrandon and Alain Roussel}, doi = {10.1074/jbc.M109.034587}, issn = {1083-351X}, year = {2009}, date = {2009-10-01}, journal = {J. Biol. Chem.}, volume = {284}, number = {42}, pages = {28687--28697}, abstract = {Gram-negative binding protein 3 (GNBP3), a pattern recognition receptor that circulates in the hemolymph of Drosophila, is responsible for sensing fungal infection and triggering Toll pathway activation. Here, we report that GNBP3 N-terminal domain binds to fungi upon identifying long chains of beta-1,3-glucans in the fungal cell wall as a major ligand. Interestingly, this domain fails to interact strongly with short oligosaccharides. The crystal structure of GNBP3-Nter reveals an immunoglobulin-like fold in which the glucan binding site is masked by a loop that is highly conserved among glucan-binding proteins identified in several insect orders. Structure-based mutagenesis experiments reveal an essential role for this occluding loop in discriminating between short and long polysaccharides. The displacement of the occluding loop is necessary for binding and could explain the specificity of the interaction with long chain structured polysaccharides. This represents a novel mechanism for beta-glucan recognition.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Gram-negative binding protein 3 (GNBP3), a pattern recognition receptor that circulates in the hemolymph of Drosophila, is responsible for sensing fungal infection and triggering Toll pathway activation. Here, we report that GNBP3 N-terminal domain binds to fungi upon identifying long chains of beta-1,3-glucans in the fungal cell wall as a major ligand. Interestingly, this domain fails to interact strongly with short oligosaccharides. The crystal structure of GNBP3-Nter reveals an immunoglobulin-like fold in which the glucan binding site is masked by a loop that is highly conserved among glucan-binding proteins identified in several insect orders. Structure-based mutagenesis experiments reveal an essential role for this occluding loop in discriminating between short and long polysaccharides. The displacement of the occluding loop is necessary for binding and could explain the specificity of the interaction with long chain structured polysaccharides. This represents a novel mechanism for beta-glucan recognition. |
| 164. | Fraiture, Malou; Baxter, Richard H G; Steinert, Stefanie; Chelliah, Yogarany; Frolet, Cécile; Quispe-Tintaya, Wilber; Hoffmann, Jules A; Blandin, Stéphanie A; Levashina, Elena A Two mosquito LRR proteins function as complement control factors in the TEP1-mediated killing of Plasmodium Article de journal Cell Host Microbe, 5 (3), p. 273–284, 2009, ISSN: 1934-6069. @article{fraiture_two_2009, title = {Two mosquito LRR proteins function as complement control factors in the TEP1-mediated killing of Plasmodium}, author = { Malou Fraiture and Richard H. G. Baxter and Stefanie Steinert and Yogarany Chelliah and Cécile Frolet and Wilber Quispe-Tintaya and Jules A. Hoffmann and Stéphanie A. Blandin and Elena A. Levashina}, doi = {10.1016/j.chom.2009.01.005}, issn = {1934-6069}, year = {2009}, date = {2009-03-01}, journal = {Cell Host Microbe}, volume = {5}, number = {3}, pages = {273--284}, abstract = {Plasmodium development within Anopheles mosquitoes is a vulnerable step in the parasite transmission cycle, and targeting this step represents a promising strategy for malaria control. The thioester-containing complement-like protein TEP1 and two leucine-rich repeat (LRR) proteins, LRIM1 and APL1, have been identified as major mosquito factors that regulate parasite loads. Here, we show that LRIM1 and APL1 are required for binding of TEP1 to parasites. RNAi silencing of the LRR-encoding genes results in deposition of TEP1 on Anopheles tissues, thereby depleting TEP1 from circulation in the hemolymph and impeding its binding to Plasmodium. LRIM1 and APL1 not only stabilize circulating TEP1, they also stabilize each other prior to their interaction with TEP1. Our results indicate that three major antiparasitic factors in mosquitoes jointly function as a complement-like system in parasite killing, and they reveal a role for LRR proteins as complement control factors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Plasmodium development within Anopheles mosquitoes is a vulnerable step in the parasite transmission cycle, and targeting this step represents a promising strategy for malaria control. The thioester-containing complement-like protein TEP1 and two leucine-rich repeat (LRR) proteins, LRIM1 and APL1, have been identified as major mosquito factors that regulate parasite loads. Here, we show that LRIM1 and APL1 are required for binding of TEP1 to parasites. RNAi silencing of the LRR-encoding genes results in deposition of TEP1 on Anopheles tissues, thereby depleting TEP1 from circulation in the hemolymph and impeding its binding to Plasmodium. LRIM1 and APL1 not only stabilize circulating TEP1, they also stabilize each other prior to their interaction with TEP1. Our results indicate that three major antiparasitic factors in mosquitoes jointly function as a complement-like system in parasite killing, and they reveal a role for LRR proteins as complement control factors. |
2008 |
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Articles de journaux |
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| 163. | Deddouche, Safia; Matt, Nicolas ; Budd, Aidan ; Mueller, Stefanie ; Kemp, Cordula ; Galiana-Arnoux, Delphine ; Dostert, Catherine ; Antoniewski, Christophe ; Hoffmann, Jules A; Imler, Jean-Luc The DExD/Ħ-box helicase Dicer-2 mediates the induction of antiviral activity in drosophila Article de journal Nature Immunology, 9 (12), p. 1425–1432, 2008, ISSN: 1529-2916. @article{deddouche_dexd/h-box_2008, title = {The DExD/Ħ-box helicase Dicer-2 mediates the induction of antiviral activity in drosophila}, author = { Safia Deddouche and Nicolas Matt and Aidan Budd and Stefanie Mueller and Cordula Kemp and Delphine Galiana-Arnoux and Catherine Dostert and Christophe Antoniewski and Jules A. Hoffmann and Jean-Luc Imler}, doi = {10.1038/ni.1664}, issn = {1529-2916}, year = {2008}, date = {2008-12-01}, journal = {Nature Immunology}, volume = {9}, number = {12}, pages = {1425--1432}, abstract = {Drosophila, like other invertebrates and plants, relies mainly on RNA interference for its defense against viruses. In flies, viral infection also triggers the expression of many genes. One of the genes induced, Vago, encodes a 18-kilodalton cysteine-rich polypeptide. Here we provide genetic evidence that the Vago gene product controlled viral load in the fat body after infection with drosophila C virus. Induction of Vago was dependent on the helicase Dicer-2. Dicer-2 belongs to the same DExD/H-box helicase family as do the RIG-I-like receptors, which sense viral infection and mediate interferon induction in mammals. We propose that this family represents an evolutionary conserved set of sensors that detect viral nucleic acids and direct antiviral responses.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Drosophila, like other invertebrates and plants, relies mainly on RNA interference for its defense against viruses. In flies, viral infection also triggers the expression of many genes. One of the genes induced, Vago, encodes a 18-kilodalton cysteine-rich polypeptide. Here we provide genetic evidence that the Vago gene product controlled viral load in the fat body after infection with drosophila C virus. Induction of Vago was dependent on the helicase Dicer-2. Dicer-2 belongs to the same DExD/H-box helicase family as do the RIG-I-like receptors, which sense viral infection and mediate interferon induction in mammals. We propose that this family represents an evolutionary conserved set of sensors that detect viral nucleic acids and direct antiviral responses. |
| 162. | Goto, Akira; Matsushita, Kazufumi ; Gesellchen, Viola ; Chamy, Laure El ; Kuttenkeuler, David ; Takeuchi, Osamu ; Hoffmann, Jules A; Akira, Shizuo ; Boutros, Michael ; Reichhart, Jean-Marc Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice Article de journal Nat. Immunol., 9 (1), p. 97–104, 2008, ISSN: 1529-2916. @article{goto_akirins_2008, title = {Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice}, author = { Akira Goto and Kazufumi Matsushita and Viola Gesellchen and Laure El Chamy and David Kuttenkeuler and Osamu Takeuchi and Jules A. Hoffmann and Shizuo Akira and Michael Boutros and Jean-Marc Reichhart}, doi = {10.1038/ni1543}, issn = {1529-2916}, year = {2008}, date = {2008-01-01}, journal = {Nat. Immunol.}, volume = {9}, number = {1}, pages = {97--104}, abstract = {During a genome-wide screen with RNA-mediated interference, we isolated CG8580 as a gene involved in the innate immune response of Drosophila melanogaster. CG8580, which we called Akirin, encoded a protein that acted in parallel with the NF-kappaB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved, and the human genome contains two homologs, one of which was able to rescue the loss-of-function phenotype in drosophila cells. Akirins were strictly localized to the nucleus. Knockout of both Akirin homologs in mice showed that one had an essential function downstream of the Toll-like receptor, tumor necrosis factor and interleukin (IL)-1beta signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses.}, keywords = {}, pubstate = {published}, tppubtype = {article} } During a genome-wide screen with RNA-mediated interference, we isolated CG8580 as a gene involved in the innate immune response of Drosophila melanogaster. CG8580, which we called Akirin, encoded a protein that acted in parallel with the NF-kappaB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved, and the human genome contains two homologs, one of which was able to rescue the loss-of-function phenotype in drosophila cells. Akirins were strictly localized to the nucleus. Knockout of both Akirin homologs in mice showed that one had an essential function downstream of the Toll-like receptor, tumor necrosis factor and interleukin (IL)-1beta signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses. |
2007 |
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Articles de journaux |
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| 161. | Ferrandon, Dominique; Imler, Jean-Luc; Hetru, Charles; Hoffmann, Jules A The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections Article de journal Nat Rev Immunol, 7 , p. 862–74, 2007. @article{ferrandon_drosophila_2007b, title = {The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections}, author = {Dominique Ferrandon and Jean-Luc Imler and Charles Hetru and Jules A. Hoffmann}, year = {2007}, date = {2007-11-01}, journal = {Nat Rev Immunol}, volume = {7}, pages = {862--74}, abstract = {A hallmark of the potent, multifaceted antimicrobial defence of Drosophila melanogaster is the challenge-induced synthesis of several families of antimicrobial peptides by cells in the fat body. The basic mechanisms of recognition of various types of microbial infections by the adult fly are now understood, often in great detail. We have further gained valuable insight into the infection-induced gene reprogramming by nuclear factor-kappaB (NF-kappaB) family members under the dependence of complex intracellular signalling cascades. The striking parallels between the adult fly response and mammalian innate immune defences described below point to a common ancestry and validate the relevance of the fly defence as a paradigm for innate immunity.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A hallmark of the potent, multifaceted antimicrobial defence of Drosophila melanogaster is the challenge-induced synthesis of several families of antimicrobial peptides by cells in the fat body. The basic mechanisms of recognition of various types of microbial infections by the adult fly are now understood, often in great detail. We have further gained valuable insight into the infection-induced gene reprogramming by nuclear factor-kappaB (NF-kappaB) family members under the dependence of complex intracellular signalling cascades. The striking parallels between the adult fly response and mammalian innate immune defences described below point to a common ancestry and validate the relevance of the fly defence as a paradigm for innate immunity. |
| 160. | Beutler, Bruce; Eidenschenk, Celine ; Crozat, Karine ; Imler, Jean-Luc ; Takeuchi, Osamu ; Hoffmann, Jules A; Akira, Shizuo Genetic analysis of resistance to viral infection Article de journal Nature Reviews. Immunology, 7 (10), p. 753–766, 2007, ISSN: 1474-1741. @article{beutler_genetic_2007, title = {Genetic analysis of resistance to viral infection}, author = { Bruce Beutler and Celine Eidenschenk and Karine Crozat and Jean-Luc Imler and Osamu Takeuchi and Jules A. Hoffmann and Shizuo Akira}, doi = {10.1038/nri2174}, issn = {1474-1741}, year = {2007}, date = {2007-10-01}, journal = {Nature Reviews. Immunology}, volume = {7}, number = {10}, pages = {753--766}, abstract = {As machines that reprogramme eukaryotic cells to suit their own purposes, viruses present a difficult problem for multicellular hosts, and indeed, have become one of the central pre-occupations of the immune system. Unable to permanently outpace individual viruses in an evolutionary footrace, higher eukaryotes have evolved broadly active mechanisms with which to sense viruses and suppress their proliferation. These mechanisms have recently been elucidated by a combination of forward and reverse genetic methods. Some of these mechanisms are clearly ancient, whereas others are relatively new. All are remarkably adept at discriminating self from non-self, and allow the host to cope with what might seem an impossible predicament.}, keywords = {}, pubstate = {published}, tppubtype = {article} } As machines that reprogramme eukaryotic cells to suit their own purposes, viruses present a difficult problem for multicellular hosts, and indeed, have become one of the central pre-occupations of the immune system. Unable to permanently outpace individual viruses in an evolutionary footrace, higher eukaryotes have evolved broadly active mechanisms with which to sense viruses and suppress their proliferation. These mechanisms have recently been elucidated by a combination of forward and reverse genetic methods. Some of these mechanisms are clearly ancient, whereas others are relatively new. All are remarkably adept at discriminating self from non-self, and allow the host to cope with what might seem an impossible predicament. |
| 159. | Nehme, Nadine T; Liégeois, Samuel; Kele, Beatrix; Giammarinaro, Philippe; Pradel, Elizabeth; Hoffmann, Jules A; Ewbank, Jonathan J; Ferrandon, Dominique A model of bacterial intestinal infections in Drosophila melanogaster Article de journal PLoS Pathog., 3 (11), p. e173, 2007, ISSN: 1553-7374. @article{nehme_model_2007b, title = {A model of bacterial intestinal infections in Drosophila melanogaster}, author = { Nadine T. Nehme and Samuel Liégeois and Beatrix Kele and Philippe Giammarinaro and Elizabeth Pradel and Jules A. Hoffmann and Jonathan J. Ewbank and Dominique Ferrandon}, doi = {10.1371/journal.ppat.0030173}, issn = {1553-7374}, year = {2007}, date = {2007-01-01}, journal = {PLoS Pathog.}, volume = {3}, number = {11}, pages = {e173}, abstract = {Serratia marcescens is an entomopathogenic bacterium that opportunistically infects a wide range of hosts, including humans. In a model of septic injury, if directly introduced into the body cavity of Drosophila, this pathogen is insensitive to the host's systemic immune response and kills flies in a day. We find that S. marcescens resistance to the Drosophila immune deficiency (imd)-mediated humoral response requires the bacterial lipopolysaccharide O-antigen. If ingested by Drosophila, bacteria cross the gut and penetrate the body cavity. During this passage, the bacteria can be observed within the cells of the intestinal epithelium. In such an oral infection model, the flies succumb to infection only after 6 days. We demonstrate that two complementary host defense mechanisms act together against such food-borne infection: an antimicrobial response in the intestine that is regulated by the imd pathway and phagocytosis by hemocytes of bacteria that have escaped into the hemolymph. Interestingly, bacteria present in the hemolymph elicit a systemic immune response only when phagocytosis is blocked. Our observations support a model wherein peptidoglycan fragments released during bacterial growth activate the imd pathway and do not back a proposed role for phagocytosis in the immune activation of the fat body. Thanks to the genetic tools available in both host and pathogen, the molecular dissection of the interactions between S. marcescens and Drosophila will provide a useful paradigm for deciphering intestinal pathogenesis.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Serratia marcescens is an entomopathogenic bacterium that opportunistically infects a wide range of hosts, including humans. In a model of septic injury, if directly introduced into the body cavity of Drosophila, this pathogen is insensitive to the host's systemic immune response and kills flies in a day. We find that S. marcescens resistance to the Drosophila immune deficiency (imd)-mediated humoral response requires the bacterial lipopolysaccharide O-antigen. If ingested by Drosophila, bacteria cross the gut and penetrate the body cavity. During this passage, the bacteria can be observed within the cells of the intestinal epithelium. In such an oral infection model, the flies succumb to infection only after 6 days. We demonstrate that two complementary host defense mechanisms act together against such food-borne infection: an antimicrobial response in the intestine that is regulated by the imd pathway and phagocytosis by hemocytes of bacteria that have escaped into the hemolymph. Interestingly, bacteria present in the hemolymph elicit a systemic immune response only when phagocytosis is blocked. Our observations support a model wherein peptidoglycan fragments released during bacterial growth activate the imd pathway and do not back a proposed role for phagocytosis in the immune activation of the fat body. Thanks to the genetic tools available in both host and pathogen, the molecular dissection of the interactions between S. marcescens and Drosophila will provide a useful paradigm for deciphering intestinal pathogenesis. |
2006 |
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| 158. | Shiao, Shin-Hong; Whitten, Miranda M A; Zachary, Daniel; Hoffmann, Jules A; Levashina, Elena A Fz2 and cdc42 mediate melanization and actin polymerization but are dispensable for Plasmodium killing in the mosquito midgut Article de journal PLoS Pathog., 2 (12), p. e133, 2006, ISSN: 1553-7374. @article{shiao_fz2_2006, title = {Fz2 and cdc42 mediate melanization and actin polymerization but are dispensable for Plasmodium killing in the mosquito midgut}, author = { Shin-Hong Shiao and Miranda M. A. Whitten and Daniel Zachary and Jules A. Hoffmann and Elena A. Levashina}, doi = {10.1371/journal.ppat.0020133}, issn = {1553-7374}, year = {2006}, date = {2006-12-01}, journal = {PLoS Pathog.}, volume = {2}, number = {12}, pages = {e133}, abstract = {The midgut epithelium of the mosquito malaria vector Anopheles is a hostile environment for Plasmodium, with most parasites succumbing to host defenses. This study addresses morphological and ultrastructural features associated with Plasmodium berghei ookinete invasion in Anopheles gambiae midguts to define the sites and possible mechanisms of parasite killing. We show by transmission electron microscopy and immunofluorescence that the majority of ookinetes are killed in the extracellular space. Dead or dying ookinetes are surrounded by a polymerized actin zone formed within the basal cytoplasm of adjacent host epithelial cells. In refractory strain mosquitoes, we found that formation of this zone is strongly linked to prophenoloxidase activation leading to melanization. Furthermore, we identify two factors controlling both phenomena: the transmembrane receptor frizzled-2 and the guanosine triphosphate-binding protein cell division cycle 42. However, the disruption of actin polymerization and melanization by double-stranded RNA inhibition did not affect ookinete survival. Our results separate the mechanisms of parasite killing from subsequent reactions manifested by actin polymerization and prophenoloxidase activation in the A. gambiae-P. berghei model. These latter processes are reminiscent of wound healing in other organisms, and we propose that they represent a form of wound-healing response directed towards a moribund ookinete, which is perceived as damaged tissue.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The midgut epithelium of the mosquito malaria vector Anopheles is a hostile environment for Plasmodium, with most parasites succumbing to host defenses. This study addresses morphological and ultrastructural features associated with Plasmodium berghei ookinete invasion in Anopheles gambiae midguts to define the sites and possible mechanisms of parasite killing. We show by transmission electron microscopy and immunofluorescence that the majority of ookinetes are killed in the extracellular space. Dead or dying ookinetes are surrounded by a polymerized actin zone formed within the basal cytoplasm of adjacent host epithelial cells. In refractory strain mosquitoes, we found that formation of this zone is strongly linked to prophenoloxidase activation leading to melanization. Furthermore, we identify two factors controlling both phenomena: the transmembrane receptor frizzled-2 and the guanosine triphosphate-binding protein cell division cycle 42. However, the disruption of actin polymerization and melanization by double-stranded RNA inhibition did not affect ookinete survival. Our results separate the mechanisms of parasite killing from subsequent reactions manifested by actin polymerization and prophenoloxidase activation in the A. gambiae-P. berghei model. These latter processes are reminiscent of wound healing in other organisms, and we propose that they represent a form of wound-healing response directed towards a moribund ookinete, which is perceived as damaged tissue. |
| 157. | Gottar, Marie; Gobert, Vanessa ; Matskevich, Alexey A; Reichhart, Jean-Marc ; Wang, Chengshu ; Butt, Tariq M; Belvin, Marcia ; Hoffmann, Jules A; Ferrandon, Dominique Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors Article de journal Cell, 127 (7), p. 1425–1437, 2006, ISSN: 0092-8674. @article{gottar_dual_2006, title = {Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors}, author = { Marie Gottar and Vanessa Gobert and Alexey A. Matskevich and Jean-Marc Reichhart and Chengshu Wang and Tariq M. Butt and Marcia Belvin and Jules A. Hoffmann and Dominique Ferrandon}, doi = {10.1016/j.cell.2006.10.046}, issn = {0092-8674}, year = {2006}, date = {2006-12-01}, journal = {Cell}, volume = {127}, number = {7}, pages = {1425--1437}, abstract = {The Drosophila immune system discriminates between various types of infections and activates appropriate signal transduction pathways to combat the invading microorganisms. The Toll pathway is required for the host response against fungal and most Gram-positive bacterial infections. The sensing of Gram-positive bacteria is mediated by the pattern recognition receptors PGRP-SA and GNBP1 that cooperate to detect the presence of infections in the host. Here, we report that GNBP3 is a pattern recognition receptor that is required for the detection of fungal cell wall components. Strikingly, we find that there is a second, parallel pathway acting jointly with GNBP3. The Drosophila Persephone protease activates the Toll pathway when proteolytically matured by the secreted fungal virulence factor PR1. Thus, the detection of fungal infections in Drosophila relies both on the recognition of invariant microbial patterns and on monitoring the effects of virulence factors on the host.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Drosophila immune system discriminates between various types of infections and activates appropriate signal transduction pathways to combat the invading microorganisms. The Toll pathway is required for the host response against fungal and most Gram-positive bacterial infections. The sensing of Gram-positive bacteria is mediated by the pattern recognition receptors PGRP-SA and GNBP1 that cooperate to detect the presence of infections in the host. Here, we report that GNBP3 is a pattern recognition receptor that is required for the detection of fungal cell wall components. Strikingly, we find that there is a second, parallel pathway acting jointly with GNBP3. The Drosophila Persephone protease activates the Toll pathway when proteolytically matured by the secreted fungal virulence factor PR1. Thus, the detection of fungal infections in Drosophila relies both on the recognition of invariant microbial patterns and on monitoring the effects of virulence factors on the host. |
| 156. | Frolet, Cécile; Thoma, Martine; Blandin, Stéphanie A; Hoffmann, Jules A; Levashina, Elena A Boosting NF-kappaB-dependent basal immunity of Anopheles gambiae aborts development of Plasmodium berghei Article de journal Immunity, 25 (4), p. 677–685, 2006, ISSN: 1074-7613. @article{frolet_boosting_2006, title = {Boosting NF-kappaB-dependent basal immunity of Anopheles gambiae aborts development of Plasmodium berghei}, author = {Cécile Frolet and Martine Thoma and Stéphanie A. Blandin and Jules A. Hoffmann and Elena A. Levashina}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17045818}, doi = {10.1016/j.immuni.2006.08.019}, issn = {1074-7613}, year = {2006}, date = {2006-10-01}, journal = {Immunity}, volume = {25}, number = {4}, pages = {677--685}, abstract = {Anopheles gambiae, the major vector for the protozoan malaria parasite Plasmodium falciparum, mounts powerful antiparasitic responses that cause marked parasite loss during midgut invasion. Here, we showed that these antiparasitic defenses were composed of pre- and postinvasion phases and that the preinvasion phase was predominantly regulated by Rel1 and Rel2 members of the NF-kappaB transcription factors. Concurrent silencing of Rel1 and Rel2 decreased the basal expression of the major antiparasitic genes TEP1 and LRIM1 and abolished resistance of Anopheles to the rodent malaria parasite P. berghei. Conversely, depletion of a negative regulator of Rel1, Cactus, prior to infection, enhanced the basal expression of TEP1 and of other immune factors and completely prevented parasite development. Our findings uncover the crucial role of the preinvasion defense in the elimination of parasites, which is at least in part based on circulating blood molecules.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Anopheles gambiae, the major vector for the protozoan malaria parasite Plasmodium falciparum, mounts powerful antiparasitic responses that cause marked parasite loss during midgut invasion. Here, we showed that these antiparasitic defenses were composed of pre- and postinvasion phases and that the preinvasion phase was predominantly regulated by Rel1 and Rel2 members of the NF-kappaB transcription factors. Concurrent silencing of Rel1 and Rel2 decreased the basal expression of the major antiparasitic genes TEP1 and LRIM1 and abolished resistance of Anopheles to the rodent malaria parasite P. berghei. Conversely, depletion of a negative regulator of Rel1, Cactus, prior to infection, enhanced the basal expression of TEP1 and of other immune factors and completely prevented parasite development. Our findings uncover the crucial role of the preinvasion defense in the elimination of parasites, which is at least in part based on circulating blood molecules. |
| 155. | Galiana-Arnoux, Delphine; Dostert, Catherine ; Schneemann, Anette ; Hoffmann, Jules A; Imler, Jean-Luc Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila Article de journal Nature Immunology, 7 (6), p. 590–597, 2006, ISSN: 1529-2908. @article{galiana-arnoux_essential_2006, title = {Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila}, author = { Delphine Galiana-Arnoux and Catherine Dostert and Anette Schneemann and Jules A. Hoffmann and Jean-Luc Imler}, doi = {10.1038/ni1335}, issn = {1529-2908}, year = {2006}, date = {2006-06-01}, journal = {Nature Immunology}, volume = {7}, number = {6}, pages = {590--597}, abstract = {The fruit fly Drosophila melanogaster is a model system for studying innate immunity, including antiviral host defense. Infection with drosophila C virus triggers a transcriptional response that is dependent in part on the Jak kinase Hopscotch. Here we show that successful infection and killing of drosophila with the insect nodavirus flock house virus was strictly dependent on expression of the viral protein B2, a potent inhibitor of processing of double-stranded RNA mediated by the essential RNA interference factor Dicer. Conversely, flies with a loss-of-function mutation in the gene encoding Dicer-2 (Dcr-2) showed enhanced susceptibility to infection by flock house virus, drosophila C virus and Sindbis virus, members of three different families of RNA viruses. These data demonstrate the importance of RNA interference for controlling virus replication in vivo and establish Dcr-2 as a host susceptibility locus for virus infections.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The fruit fly Drosophila melanogaster is a model system for studying innate immunity, including antiviral host defense. Infection with drosophila C virus triggers a transcriptional response that is dependent in part on the Jak kinase Hopscotch. Here we show that successful infection and killing of drosophila with the insect nodavirus flock house virus was strictly dependent on expression of the viral protein B2, a potent inhibitor of processing of double-stranded RNA mediated by the essential RNA interference factor Dicer. Conversely, flies with a loss-of-function mutation in the gene encoding Dicer-2 (Dcr-2) showed enhanced susceptibility to infection by flock house virus, drosophila C virus and Sindbis virus, members of three different families of RNA viruses. These data demonstrate the importance of RNA interference for controlling virus replication in vivo and establish Dcr-2 as a host susceptibility locus for virus infections. |
| 154. | Bischoff, Vincent; Vignal, Cécile; Duvic, Bernard; Boneca, Ivo G; Hoffmann, Jules A; Royet, Julien Downregulation of the Drosophila immune response by peptidoglycan-recognition proteins SC1 and SC2 Article de journal PLoS Pathog., 2 (2), p. e14, 2006, ISSN: 1553-7374. @article{bischoff_downregulation_2006, title = {Downregulation of the Drosophila immune response by peptidoglycan-recognition proteins SC1 and SC2}, author = { Vincent Bischoff and Cécile Vignal and Bernard Duvic and Ivo G. Boneca and Jules A. Hoffmann and Julien Royet}, doi = {10.1371/journal.ppat.0020014}, issn = {1553-7374}, year = {2006}, date = {2006-02-01}, journal = {PLoS Pathog.}, volume = {2}, number = {2}, pages = {e14}, abstract = {Peptidoglycan-recognition proteins (PGRPs) are evolutionarily conserved molecules that are structurally related to bacterial amidases. Several Drosophila PGRPs have lost this enzymatic activity and serve as microbe sensors through peptidoglycan recognition. Other PGRP family members, such as Drosophila PGRP-SC1 or mammalian PGRP-L, have conserved the amidase function and are able to cleave peptidoglycan in vitro. However, the contribution of these amidase PGRPs to host defense in vivo has remained elusive so far. Using an RNA-interference approach, we addressed the function of two PGRPs with amidase activity in the Drosophila immune response. We observed that PGRP-SC1/2-depleted flies present a specific over-activation of the IMD (immune deficiency) signaling pathway after bacterial challenge. Our data suggest that these proteins act in the larval gut to prevent activation of this pathway following bacterial ingestion. We further show that a strict control of IMD-pathway activation is essential to prevent bacteria-induced developmental defects and larval death.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Peptidoglycan-recognition proteins (PGRPs) are evolutionarily conserved molecules that are structurally related to bacterial amidases. Several Drosophila PGRPs have lost this enzymatic activity and serve as microbe sensors through peptidoglycan recognition. Other PGRP family members, such as Drosophila PGRP-SC1 or mammalian PGRP-L, have conserved the amidase function and are able to cleave peptidoglycan in vitro. However, the contribution of these amidase PGRPs to host defense in vivo has remained elusive so far. Using an RNA-interference approach, we addressed the function of two PGRPs with amidase activity in the Drosophila immune response. We observed that PGRP-SC1/2-depleted flies present a specific over-activation of the IMD (immune deficiency) signaling pathway after bacterial challenge. Our data suggest that these proteins act in the larval gut to prevent activation of this pathway following bacterial ingestion. We further show that a strict control of IMD-pathway activation is essential to prevent bacteria-induced developmental defects and larval death. |
| 153. | Leclerc, Vincent; Pelte, Nadège ; Chamy, Laure El ; Martinelli, Cosimo ; Ligoxygakis, Petros ; Hoffmann, Jules A; Reichhart, Jean-Marc Prophenoloxidase activation is not required for survival to microbial infections in Drosophila Article de journal EMBO Rep., 7 (2), p. 231–235, 2006, ISSN: 1469-221X. @article{leclerc_prophenoloxidase_2006, title = {Prophenoloxidase activation is not required for survival to microbial infections in Drosophila}, author = { Vincent Leclerc and Nadège Pelte and Laure El Chamy and Cosimo Martinelli and Petros Ligoxygakis and Jules A. Hoffmann and Jean-Marc Reichhart}, doi = {10.1038/sj.embor.7400592}, issn = {1469-221X}, year = {2006}, date = {2006-02-01}, journal = {EMBO Rep.}, volume = {7}, number = {2}, pages = {231--235}, abstract = {The antimicrobial defence of Drosophila relies on cellular and humoral processes, of which the inducible synthesis of antimicrobial peptides has attracted interest in recent years. Another potential line of defence is the activation, by a proteolytic cascade, of phenoloxidase, which leads to the production of quinones and melanin. However, in spite of several publications on this subject, the contribution of phenoloxidase activation to resistance to infections has not been established under appropriate in vivo conditions. Here, we have isolated the first Drosophila mutant for a prophenoloxidase-activating enzyme (PAE1). In contrast to wild-type flies, PAE1 mutants fail to activate phenoloxidase in the haemolymph following microbial challenge. Surprisingly, we find that these mutants are as resistant to infections as wild-type flies, in the total absence of circulating phenoloxidase activity. This raises the question with regard to the precise function of phenoloxidase activation in defence, if any.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The antimicrobial defence of Drosophila relies on cellular and humoral processes, of which the inducible synthesis of antimicrobial peptides has attracted interest in recent years. Another potential line of defence is the activation, by a proteolytic cascade, of phenoloxidase, which leads to the production of quinones and melanin. However, in spite of several publications on this subject, the contribution of phenoloxidase activation to resistance to infections has not been established under appropriate in vivo conditions. Here, we have isolated the first Drosophila mutant for a prophenoloxidase-activating enzyme (PAE1). In contrast to wild-type flies, PAE1 mutants fail to activate phenoloxidase in the haemolymph following microbial challenge. Surprisingly, we find that these mutants are as resistant to infections as wild-type flies, in the total absence of circulating phenoloxidase activity. This raises the question with regard to the precise function of phenoloxidase activation in defence, if any. |
2005 |
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| 152. | Kocks, Christine; Cho, Ju Hyun ; Nehme, Nadine ; Ulvila, Johanna ; Pearson, Alan M; Meister, Marie ; Strom, Charles ; Conto, Stephanie L; Hetru, Charles ; Stuart, Lynda M; Stehle, Thilo ; Hoffmann, Jules A; Reichhart, Jean-Marc ; Ferrandon, Dominique ; Rämet, Mika ; Ezekowitz, Alan R B Eater, a transmembrane protein mediating phagocytosis of bacterial pathogens in Drosophila Article de journal Cell, 123 (2), p. 335–346, 2005, ISSN: 0092-8674. @article{kocks_eater_2005, title = {Eater, a transmembrane protein mediating phagocytosis of bacterial pathogens in Drosophila}, author = { Christine Kocks and Ju Hyun Cho and Nadine Nehme and Johanna Ulvila and Alan M. Pearson and Marie Meister and Charles Strom and Stephanie L. Conto and Charles Hetru and Lynda M. Stuart and Thilo Stehle and Jules A. Hoffmann and Jean-Marc Reichhart and Dominique Ferrandon and Mika Rämet and R. Alan B. Ezekowitz}, doi = {10.1016/j.cell.2005.08.034}, issn = {0092-8674}, year = {2005}, date = {2005-10-01}, journal = {Cell}, volume = {123}, number = {2}, pages = {335--346}, abstract = {Phagocytosis is a complex, evolutionarily conserved process that plays a central role in host defense against infection. We have identified a predicted transmembrane protein, Eater, which is involved in phagocytosis in Drosophila. Transcriptional silencing of the eater gene in a macrophage cell line led to a significant reduction in the binding and internalization of bacteria. Moreover, the N terminus of the Eater protein mediated direct microbial binding which could be inhibited with scavenger receptor ligands, acetylated, and oxidized low-density lipoprotein. In vivo, eater expression was restricted to blood cells. Flies lacking the eater gene displayed normal responses in NF-kappaB-like Toll and IMD signaling pathways but showed impaired phagocytosis and decreased survival after bacterial infection. Our results suggest that Eater is a major phagocytic receptor for a broad range of bacterial pathogens in Drosophila and provide a powerful model to address the role of phagocytosis in vivo.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Phagocytosis is a complex, evolutionarily conserved process that plays a central role in host defense against infection. We have identified a predicted transmembrane protein, Eater, which is involved in phagocytosis in Drosophila. Transcriptional silencing of the eater gene in a macrophage cell line led to a significant reduction in the binding and internalization of bacteria. Moreover, the N terminus of the Eater protein mediated direct microbial binding which could be inhibited with scavenger receptor ligands, acetylated, and oxidized low-density lipoprotein. In vivo, eater expression was restricted to blood cells. Flies lacking the eater gene displayed normal responses in NF-kappaB-like Toll and IMD signaling pathways but showed impaired phagocytosis and decreased survival after bacterial infection. Our results suggest that Eater is a major phagocytic receptor for a broad range of bacterial pathogens in Drosophila and provide a powerful model to address the role of phagocytosis in vivo. |
| 151. | Irving, Phil; Ubeda, Jean-Michel; Doucet, Daniel; Troxler, Laurent; Lagueux, Marie; Zachary, Daniel; Hoffmann, Jules A; Hetru, Charles; Meister, Marie New insights into Drosophila larval haemocyte functions through genome-wide analysis Article de journal Cell. Microbiol., 7 (3), p. 335–350, 2005, ISSN: 1462-5814. @article{irving_new_2005, title = {New insights into Drosophila larval haemocyte functions through genome-wide analysis}, author = { Phil Irving and Jean-Michel Ubeda and Daniel Doucet and Laurent Troxler and Marie Lagueux and Daniel Zachary and Jules A. Hoffmann and Charles Hetru and Marie Meister}, doi = {10.1111/j.1462-5822.2004.00462.x}, issn = {1462-5814}, year = {2005}, date = {2005-03-01}, journal = {Cell. Microbiol.}, volume = {7}, number = {3}, pages = {335--350}, abstract = {Drosophila blood cells or haemocytes comprise three cell lineages, plasmatocytes, crystal cells and lamellocytes, involved in immune functions such as phagocytosis, melanisation and encapsulation. Transcriptional profiling of activities of distinct haemocyte populations and from naive or infected larvae, was performed to find genes contributing to haemocyte functions. Of the 13 000 genes represented on the microarray, over 2500 exhibited significantly enriched transcription in haemocytes. Among these were genes encoding integrins, peptidoglycan recognition proteins (PGRPs), scavenger receptors, lectins, cell adhesion molecules and serine proteases. One relevant outcome of this analysis was the gain of new insights into the lamellocyte encapsulation process. We showed that lamellocytes require betaPS integrin for encapsulation and that they transcribe one prophenoloxidase gene enabling them to produce the enzyme necessary for melanisation of the capsule. A second compelling observation was that following infection, the gene encoding the cytokine Spatzle was uniquely upregulated in haemocytes and not the fat body. This shows that Drosophila haemocytes produce a signal molecule ready to be activated through cleavage after pathogen recognition, informing distant tissues of infection.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Drosophila blood cells or haemocytes comprise three cell lineages, plasmatocytes, crystal cells and lamellocytes, involved in immune functions such as phagocytosis, melanisation and encapsulation. Transcriptional profiling of activities of distinct haemocyte populations and from naive or infected larvae, was performed to find genes contributing to haemocyte functions. Of the 13 000 genes represented on the microarray, over 2500 exhibited significantly enriched transcription in haemocytes. Among these were genes encoding integrins, peptidoglycan recognition proteins (PGRPs), scavenger receptors, lectins, cell adhesion molecules and serine proteases. One relevant outcome of this analysis was the gain of new insights into the lamellocyte encapsulation process. We showed that lamellocytes require betaPS integrin for encapsulation and that they transcribe one prophenoloxidase gene enabling them to produce the enzyme necessary for melanisation of the capsule. A second compelling observation was that following infection, the gene encoding the cytokine Spatzle was uniquely upregulated in haemocytes and not the fat body. This shows that Drosophila haemocytes produce a signal molecule ready to be activated through cleavage after pathogen recognition, informing distant tissues of infection. |
| 150. | Royet, Julien; Reichhart, Jean-Marc ; Hoffmann, Jules A Sensing and signaling during infection in Drosophila Article de journal Curr. Opin. Immunol., 17 (1), p. 11–17, 2005, ISSN: 0952-7915. @article{royet_sensing_2005, title = {Sensing and signaling during infection in Drosophila}, author = { Julien Royet and Jean-Marc Reichhart and Jules A. Hoffmann}, doi = {10.1016/j.coi.2004.12.002}, issn = {0952-7915}, year = {2005}, date = {2005-02-01}, journal = {Curr. Opin. Immunol.}, volume = {17}, number = {1}, pages = {11--17}, abstract = {Most of the progress in dissecting the Drosophila antimicrobial response over the past decade has centered around intracellular signaling pathways in immune response tissues and expression of genes encoding antimicrobial peptide genes. The past few years, however, have witnessed significant advances in our understanding of the recognition of microbial invaders and subsequent activation of signaling cascades. In particular, the roles of peptidoglycan recognition proteins, which have known homologues in mammals, have been recognized and examined at the structural and functional levels.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Most of the progress in dissecting the Drosophila antimicrobial response over the past decade has centered around intracellular signaling pathways in immune response tissues and expression of genes encoding antimicrobial peptide genes. The past few years, however, have witnessed significant advances in our understanding of the recognition of microbial invaders and subsequent activation of signaling cascades. In particular, the roles of peptidoglycan recognition proteins, which have known homologues in mammals, have been recognized and examined at the structural and functional levels. |
| 149. | Dostert, Catherine; Jouanguy, Emmanuelle ; Irving, Phil ; Troxler, Laurent ; Galiana-Arnoux, Delphine ; Hetru, Charles ; Hoffmann, Jules A; Imler, Jean-Luc The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of drosophila Article de journal Nature Immunology, 6 (9), p. 946–953, 2005, ISSN: 1529-2908. @article{dostert_jak-stat_2005, title = {The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of drosophila}, author = { Catherine Dostert and Emmanuelle Jouanguy and Phil Irving and Laurent Troxler and Delphine Galiana-Arnoux and Charles Hetru and Jules A. Hoffmann and Jean-Luc Imler}, doi = {10.1038/ni1237}, issn = {1529-2908}, year = {2005}, date = {2005-01-01}, journal = {Nature Immunology}, volume = {6}, number = {9}, pages = {946--953}, abstract = {The response of drosophila to bacterial and fungal infections involves two signaling pathways, Toll and Imd, which both activate members of the transcription factor NF-kappaB family. Here we have studied the global transcriptional response of flies to infection with drosophila C virus. Viral infection induced a set of genes distinct from those regulated by the Toll or Imd pathways and triggered a signal transducer and activator of transcription (STAT) DNA-binding activity. Genetic experiments showed that the Jak kinase Hopscotch was involved in the control of the viral load in infected flies and was required but not sufficient for the induction of some virus-regulated genes. Our results indicate that in addition to Toll and Imd, a third, evolutionary conserved innate immunity pathway functions in drosophila and counters viral infection.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The response of drosophila to bacterial and fungal infections involves two signaling pathways, Toll and Imd, which both activate members of the transcription factor NF-kappaB family. Here we have studied the global transcriptional response of flies to infection with drosophila C virus. Viral infection induced a set of genes distinct from those regulated by the Toll or Imd pathways and triggered a signal transducer and activator of transcription (STAT) DNA-binding activity. Genetic experiments showed that the Jak kinase Hopscotch was involved in the control of the viral load in infected flies and was required but not sufficient for the induction of some virus-regulated genes. Our results indicate that in addition to Toll and Imd, a third, evolutionary conserved innate immunity pathway functions in drosophila and counters viral infection. |
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| 148. | Bischoff, Vincent; Vignal, Cécile; Boneca, Ivo G; Michel, Tatiana; Hoffmann, Jules A; Royet, Julien Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria Article de journal Nat. Immunol., 5 (11), p. 1175–1180, 2004, ISSN: 1529-2908. @article{bischoff_function_2004, title = {Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria}, author = { Vincent Bischoff and Cécile Vignal and Ivo G. Boneca and Tatiana Michel and Jules A. Hoffmann and Julien Royet}, doi = {10.1038/ni1123}, issn = {1529-2908}, year = {2004}, date = {2004-11-01}, journal = {Nat. Immunol.}, volume = {5}, number = {11}, pages = {1175--1180}, abstract = {The activation of an immune response requires recognition of microorganisms by host receptors. In drosophila, detection of Gram-positive bacteria is mediated by cooperation between the peptidoglycan-recognition protein-SA (PGRP-SA) and Gram-negative binding protein 1 (GNBP1) proteins. Here we show that some Gram-positive bacterial species activate an immune response in a PGRP-SA- and GNBP1-independent manner, indicating that alternative receptors exist. Consistent with this, we noted that PGRP-SD mutants were susceptible to some Gram-positive bacteria and that a loss-of-function mutation in PGRP-SD severely exacerbated the PGRP-SA and GNBP1 mutant phenotypes. These data indicate that PGRP-SD can function as a receptor for Gram-positive bacteria and shows partial redundancy with the PGRP-SA-GNBP1 complex.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The activation of an immune response requires recognition of microorganisms by host receptors. In drosophila, detection of Gram-positive bacteria is mediated by cooperation between the peptidoglycan-recognition protein-SA (PGRP-SA) and Gram-negative binding protein 1 (GNBP1) proteins. Here we show that some Gram-positive bacterial species activate an immune response in a PGRP-SA- and GNBP1-independent manner, indicating that alternative receptors exist. Consistent with this, we noted that PGRP-SD mutants were susceptible to some Gram-positive bacteria and that a loss-of-function mutation in PGRP-SD severely exacerbated the PGRP-SA and GNBP1 mutant phenotypes. These data indicate that PGRP-SD can function as a receptor for Gram-positive bacteria and shows partial redundancy with the PGRP-SA-GNBP1 complex. |
| 147. | Levy, Francine; Rabel, David; Charlet, Maurice; Bulet, Philippe; Hoffmann, Jules A; Ehret-Sabatier, Laurence Peptidomic and proteomic analyses of the systemic immune response of Drosophila Article de journal Biochimie, 86 (9-10), p. 607–616, 2004, ISSN: 0300-9084. @article{levy_peptidomic_2004, title = {Peptidomic and proteomic analyses of the systemic immune response of Drosophila}, author = { Francine Levy and David Rabel and Maurice Charlet and Philippe Bulet and Jules A. Hoffmann and Laurence Ehret-Sabatier}, doi = {10.1016/j.biochi.2004.07.007}, issn = {0300-9084}, year = {2004}, date = {2004-10-01}, journal = {Biochimie}, volume = {86}, number = {9-10}, pages = {607--616}, abstract = {Insects have developed an efficient host defense against microorganisms, which involves humoral and cellular mechanisms. Numerous data highlight similarities between defense responses of insects and innate immunity of mammals. The fruit fly, Drosophila melanogaster, is a favorable model system for the analysis of the first line defense against microorganisms. Taking advantages of improvements in mass spectrometry (MS), two-dimensional (2D) gel electrophoresis and bioinformatics, differential analyses of blood content (hemolymph) from immune-challenged versus control Drosophila were performed. Two strategies were developed: (i) peptidomic analyses through matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS and high performance liquid chromatography for molecules below 15 kDa, and (ii) proteomic studies based on 2D gel electrophoresis, MALDI-TOF fingerprinting and database searches, for compounds of greater molecular masses. The peptidomic strategy led to the detection of a large number of peptides induced in the hemolymph of challenged flies as compared to controls. Of these, 28 were characterized, amongst which were antimicrobial peptides. The 2D gel electrophoresis strategy led to the detection of 70 spots differentially regulated by at least fivefold after microbial infection. This approach yielded the identity of a series of proteins that were related to the Drosophila immune response, such as proteases, protease inhibitors, prophenoloxydase-activating enzymes, serpins and a Gram-negative binding protein-like protein. This strategy also brought to light new candidates with a potential function in the immune response (odorant-binding protein, peptidylglycine alpha-hydroxylating monooxygenase and transferrin). Interestingly, several molecules resulting from the cleavage of proteins were detected after a fungal infection. Together, peptidomic and proteomic analyses represent new tools to characterize molecules involved in the innate immune reactions of Drosophila.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Insects have developed an efficient host defense against microorganisms, which involves humoral and cellular mechanisms. Numerous data highlight similarities between defense responses of insects and innate immunity of mammals. The fruit fly, Drosophila melanogaster, is a favorable model system for the analysis of the first line defense against microorganisms. Taking advantages of improvements in mass spectrometry (MS), two-dimensional (2D) gel electrophoresis and bioinformatics, differential analyses of blood content (hemolymph) from immune-challenged versus control Drosophila were performed. Two strategies were developed: (i) peptidomic analyses through matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS and high performance liquid chromatography for molecules below 15 kDa, and (ii) proteomic studies based on 2D gel electrophoresis, MALDI-TOF fingerprinting and database searches, for compounds of greater molecular masses. The peptidomic strategy led to the detection of a large number of peptides induced in the hemolymph of challenged flies as compared to controls. Of these, 28 were characterized, amongst which were antimicrobial peptides. The 2D gel electrophoresis strategy led to the detection of 70 spots differentially regulated by at least fivefold after microbial infection. This approach yielded the identity of a series of proteins that were related to the Drosophila immune response, such as proteases, protease inhibitors, prophenoloxydase-activating enzymes, serpins and a Gram-negative binding protein-like protein. This strategy also brought to light new candidates with a potential function in the immune response (odorant-binding protein, peptidylglycine alpha-hydroxylating monooxygenase and transferrin). Interestingly, several molecules resulting from the cleavage of proteins were detected after a fungal infection. Together, peptidomic and proteomic analyses represent new tools to characterize molecules involved in the innate immune reactions of Drosophila. |
| 146. | Imler, Jean-Luc; Ferrandon, Dominique ; Royet, Julien ; Reichhart, Jean-Marc ; Hetru, Charles ; Hoffmann, Jules A Toll-dependent and Toll-independent immune responses in Drosophila Article de journal Journal of Endotoxin Research, 10 (4), p. 241–246, 2004, ISSN: 0968-0519. @article{imler_toll-dependent_2004, title = {Toll-dependent and Toll-independent immune responses in Drosophila}, author = { Jean-Luc Imler and Dominique Ferrandon and Julien Royet and Jean-Marc Reichhart and Charles Hetru and Jules A. Hoffmann}, doi = {10.1179/096805104225005887}, issn = {0968-0519}, year = {2004}, date = {2004-01-01}, journal = {Journal of Endotoxin Research}, volume = {10}, number = {4}, pages = {241--246}, abstract = {The multifaceted response of the fruitfly Drosophila melanogaster to infection by a wide range of microbes is complex and remarkably efficient. Its most prominent aspect is the immune-inducible expression of a set of potent antimicrobial peptides. Genetic analysis of the regulation of the genes encoding these peptides has led to the identification of the receptor Toll as an essential component of the fly's host defense system. In addition, these studies have revealed that the response to Gram-negative bacterial infections involves Toll-independent mechanisms, and that the sensing of infection involves two structurally distinct sets of molecules--the PGRPs and the GNBPs/betaGRPs.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The multifaceted response of the fruitfly Drosophila melanogaster to infection by a wide range of microbes is complex and remarkably efficient. Its most prominent aspect is the immune-inducible expression of a set of potent antimicrobial peptides. Genetic analysis of the regulation of the genes encoding these peptides has led to the identification of the receptor Toll as an essential component of the fly's host defense system. In addition, these studies have revealed that the response to Gram-negative bacterial infections involves Toll-independent mechanisms, and that the sensing of infection involves two structurally distinct sets of molecules--the PGRPs and the GNBPs/betaGRPs. |
| 145. | Ferrandon, Dominique; Imler, Jean-Luc; Hoffmann, Jules A Sensing infection in Drosophila: Toll and beyond Article de journal Semin Immunol, 16 , p. 43–53, 2004, ISSN: 1044-5323. @article{ferrandon_sensing_2004b, title = {Sensing infection in Drosophila: Toll and beyond}, author = {Dominique Ferrandon and Jean-Luc Imler and Jules A. Hoffmann}, issn = {1044-5323}, year = {2004}, date = {2004-01-01}, journal = {Semin Immunol}, volume = {16}, pages = {43--53}, abstract = {Drosophila has evolved a potent immune system that is somewhat adapted to the nature of infections through the selective activation of either one of two NF-kappa B-like signalling pathways, the Toll and IMD (Immune deficiency) pathways. In contrast to the mammalian system, the Toll receptor does not act as a pattern recognition receptor (PRR) but as a cytokine receptor. The sensing of microbial infections is achieved by at least four PRRs that belong to two distinct families: the peptidoglycan recognition proteins (PGRPs) and the Gram-negative binding proteins (GNBPs)/beta-glucan recognition proteins (beta GRPs).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Drosophila has evolved a potent immune system that is somewhat adapted to the nature of infections through the selective activation of either one of two NF-kappa B-like signalling pathways, the Toll and IMD (Immune deficiency) pathways. In contrast to the mammalian system, the Toll receptor does not act as a pattern recognition receptor (PRR) but as a cytokine receptor. The sensing of microbial infections is achieved by at least four PRRs that belong to two distinct families: the peptidoglycan recognition proteins (PGRPs) and the Gram-negative binding proteins (GNBPs)/beta-glucan recognition proteins (beta GRPs). |
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| 144. | Gobert, Vanessa; Gottar, Marie; Matskevich, Alexey A; Rutschmann, Sophie; Royet, Julien; Belvin, Marcia; Hoffmann, Jules A; Ferrandon, Dominique Dual activation of the Drosophila toll pathway by two pattern recognition receptors Article de journal Science, 302 (5653), p. 2126–2130, 2003, ISSN: 1095-9203. @article{gobert_dual_2003, title = {Dual activation of the Drosophila toll pathway by two pattern recognition receptors}, author = { Vanessa Gobert and Marie Gottar and Alexey A. Matskevich and Sophie Rutschmann and Julien Royet and Marcia Belvin and Jules A. Hoffmann and Dominique Ferrandon}, doi = {10.1126/science.1085432}, issn = {1095-9203}, year = {2003}, date = {2003-12-01}, journal = {Science}, volume = {302}, number = {5653}, pages = {2126--2130}, abstract = {The Toll-dependent defense against Gram-positive bacterial infections in Drosophila is mediated through the peptidoglycan recognition protein SA (PGRP-SA). A mutation termed osiris disrupts the Gram-negative binding protein 1 (GNBP1) gene and leads to compromised survival of mutant flies after Gram-positive infections, but not after fungal or Gram-negative bacterial challenge. Our results demonstrate that GNBP1 and PGRP-SA can jointly activate the Toll pathway. The potential for a combination of distinct proteins to mediate detection of infectious nonself in the fly will refine the concept of pattern recognition in insects.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Toll-dependent defense against Gram-positive bacterial infections in Drosophila is mediated through the peptidoglycan recognition protein SA (PGRP-SA). A mutation termed osiris disrupts the Gram-negative binding protein 1 (GNBP1) gene and leads to compromised survival of mutant flies after Gram-positive infections, but not after fungal or Gram-negative bacterial challenge. Our results demonstrate that GNBP1 and PGRP-SA can jointly activate the Toll pathway. The potential for a combination of distinct proteins to mediate detection of infectious nonself in the fly will refine the concept of pattern recognition in insects. |
| 143. | Thouzeau, Cécile; Maho, Yvon Le; Froget, Guillaume; Sabatier, Laurence; Bohec, Céline Le; Hoffmann, Jules A; Bulet, Philippe Spheniscins, avian beta-defensins in preserved stomach contents of the king penguin, Aptenodytes patagonicus Article de journal J. Biol. Chem., 278 (51), p. 51053–51058, 2003, ISSN: 0021-9258. @article{thouzeau_spheniscins_2003, title = {Spheniscins, avian beta-defensins in preserved stomach contents of the king penguin, Aptenodytes patagonicus}, author = { Cécile Thouzeau and Yvon Le Maho and Guillaume Froget and Laurence Sabatier and Céline Le Bohec and Jules A. Hoffmann and Philippe Bulet}, doi = {10.1074/jbc.M306839200}, issn = {0021-9258}, year = {2003}, date = {2003-12-01}, journal = {J. Biol. Chem.}, volume = {278}, number = {51}, pages = {51053--51058}, abstract = {During the last part of egg incubation in king penguins, the male can preserve undigested food in the stomach for several weeks. This ensures survival of the newly hatched chick, in cases where the return of the foraging female from the sea is delayed. In accordance with the characterization of stress-induced bacteria, we demonstrate the occurrence of strong antimicrobial activities in preserved stomach contents. We isolated and fully characterized two isoforms of a novel 38-residue antimicrobial peptide (AMP), spheniscin, belonging to the beta-defensin subfamily. Spheniscin concentration was found to strongly increase during the period of food storage. Using a synthetic version of one of two spheniscin isoforms, we established that this peptide has a broad activity spectrum, affecting the growth of both pathogenic bacteria and fungi. Altogether, our data suggest that spheniscins and other, not yet identified, antimicrobial substances may play a role in the long term preservation of stored food in the stomach of king penguins.}, keywords = {}, pubstate = {published}, tppubtype = {article} } During the last part of egg incubation in king penguins, the male can preserve undigested food in the stomach for several weeks. This ensures survival of the newly hatched chick, in cases where the return of the foraging female from the sea is delayed. In accordance with the characterization of stress-induced bacteria, we demonstrate the occurrence of strong antimicrobial activities in preserved stomach contents. We isolated and fully characterized two isoforms of a novel 38-residue antimicrobial peptide (AMP), spheniscin, belonging to the beta-defensin subfamily. Spheniscin concentration was found to strongly increase during the period of food storage. Using a synthetic version of one of two spheniscin isoforms, we established that this peptide has a broad activity spectrum, affecting the growth of both pathogenic bacteria and fungi. Altogether, our data suggest that spheniscins and other, not yet identified, antimicrobial substances may play a role in the long term preservation of stored food in the stomach of king penguins. |
| 142. | Hoffmann, Jules A The immune response of Drosophila Article de journal Nature, 426 (6962), p. 33–38, 2003, ISSN: 1476-4687. @article{hoffmann_immune_2003, title = {The immune response of Drosophila}, author = { Jules A. Hoffmann}, doi = {10.1038/nature02021}, issn = {1476-4687}, year = {2003}, date = {2003-11-01}, journal = {Nature}, volume = {426}, number = {6962}, pages = {33--38}, abstract = {Drosophila mounts a potent host defence when challenged by various microorganisms. Analysis of this defence by molecular genetics has now provided a global picture of the mechanisms by which this insect senses infection, discriminates between various classes of microorganisms and induces the production of effector molecules, among which antimicrobial peptides are prominent. An unexpected result of these studies was the discovery that most of the genes involved in the Drosophila host defence are homologous or very similar to genes implicated in mammalian innate immune defences. Recent progress in research on Drosophila immune defence provides evidence for similarities and differences between Drosophila immune responses and mammalian innate immunity.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Drosophila mounts a potent host defence when challenged by various microorganisms. Analysis of this defence by molecular genetics has now provided a global picture of the mechanisms by which this insect senses infection, discriminates between various classes of microorganisms and induces the production of effector molecules, among which antimicrobial peptides are prominent. An unexpected result of these studies was the discovery that most of the genes involved in the Drosophila host defence are homologous or very similar to genes implicated in mammalian innate immune defences. Recent progress in research on Drosophila immune defence provides evidence for similarities and differences between Drosophila immune responses and mammalian innate immunity. |
| 141. | Weber, Alexander N R; Tauszig-Delamasure, Servane ; Hoffmann, Jules A; Lelièvre, Eric ; Gascan, Hugues ; Ray, Keith P; Morse, Mary A; Imler, Jean-Luc ; Gay, Nicholas J Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling Article de journal Nature Immunology, 4 (8), p. 794–800, 2003, ISSN: 1529-2908. @article{weber_binding_2003, title = {Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling}, author = { Alexander N. R. Weber and Servane Tauszig-Delamasure and Jules A. Hoffmann and Eric Lelièvre and Hugues Gascan and Keith P. Ray and Mary A. Morse and Jean-Luc Imler and Nicholas J. Gay}, doi = {10.1038/ni955}, issn = {1529-2908}, year = {2003}, date = {2003-08-01}, journal = {Nature Immunology}, volume = {4}, number = {8}, pages = {794--800}, abstract = {The extracellular protein Spätzle is required for activation of the Toll signaling pathway in the embryonic development and innate immune defense of Drosophila. Spätzle is synthesized as a pro-protein and is processed to a functional form by a serine protease. We show here that the mature form of Spätzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. Spätzle specifically bound to Drosophila cells and to Cos-7 cells expressing Toll. Furthermore, in vitro experiments showed that the mature form of Spätzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one Spätzle dimer to two receptors. The Spätzle pro-protein was inactive in all these assays, indicating that the pro-domain sequence, which is natively unstructured, acts to prevent interaction of the cytokine and its receptor Toll. These results show that, in contrast to the human Toll-like receptors, Drosophila Toll requires only an endogenous protein ligand for activation and signaling.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The extracellular protein Spätzle is required for activation of the Toll signaling pathway in the embryonic development and innate immune defense of Drosophila. Spätzle is synthesized as a pro-protein and is processed to a functional form by a serine protease. We show here that the mature form of Spätzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. Spätzle specifically bound to Drosophila cells and to Cos-7 cells expressing Toll. Furthermore, in vitro experiments showed that the mature form of Spätzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one Spätzle dimer to two receptors. The Spätzle pro-protein was inactive in all these assays, indicating that the pro-domain sequence, which is natively unstructured, acts to prevent interaction of the cytokine and its receptor Toll. These results show that, in contrast to the human Toll-like receptors, Drosophila Toll requires only an endogenous protein ligand for activation and signaling. |
| 140. | Hetru, Charles; Troxler, Laurent; Hoffmann, Jules A Drosophila melanogaster antimicrobial defense Article de journal J. Infect. Dis., 187 Suppl 2 , p. S327–334, 2003, ISSN: 0022-1899. @article{hetru_drosophila_2003, title = {Drosophila melanogaster antimicrobial defense}, author = { Charles Hetru and Laurent Troxler and Jules A. Hoffmann}, doi = {10.1086/374758}, issn = {0022-1899}, year = {2003}, date = {2003-06-01}, journal = {J. Infect. Dis.}, volume = {187 Suppl 2}, pages = {S327--334}, abstract = {The Drosophila melanogaster host defense is complex but remarkably efficient. It is a multifaceted response to a variety of fungal, bacterial, and parasitic invaders. Current knowledge is discussed on recognition of infectious microorganisms and on the activation of intracellular signaling cascades that concur with the expression of numerous immune-responsive genes, among which, to date, the most prominent appear to encode potent antimicrobial peptides.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Drosophila melanogaster host defense is complex but remarkably efficient. It is a multifaceted response to a variety of fungal, bacterial, and parasitic invaders. Current knowledge is discussed on recognition of infectious microorganisms and on the activation of intracellular signaling cascades that concur with the expression of numerous immune-responsive genes, among which, to date, the most prominent appear to encode potent antimicrobial peptides. |
| 139. | Kurz, Léopold C; Chauvet, Sophie; Andrès, Emmanuel; Aurouze, Marianne; Vallet, Isabelle; Michel, Gérard P F; Uh, Mitch; Celli, Jean; Filloux, Alain; Bentzmann, Sophie De; Steinmetz, Ivo; Hoffmann, Jules A; Finlay, Brett B; Gorvel, Jean-Pierre; Ferrandon, Dominique; Ewbank, Jonathan J Virulence factors of the human opportunistic pathogen Serratia marcescens identified by in vivo screening Article de journal Embo J, 22 , p. 1451–60, 2003, ISBN: 0261-4189. @article{kurz_virulence_2003b, title = {Virulence factors of the human opportunistic pathogen Serratia marcescens identified by in vivo screening}, author = {C. Léopold Kurz and Sophie Chauvet and Emmanuel Andrès and Marianne Aurouze and Isabelle Vallet and Gérard P. F. Michel and Mitch Uh and Jean Celli and Alain Filloux and Sophie De Bentzmann and Ivo Steinmetz and Jules A. Hoffmann and B. Brett Finlay and Jean-Pierre Gorvel and Dominique Ferrandon and Jonathan J. Ewbank}, doi = {10.1093/emboj/cdg159}, isbn = {0261-4189}, year = {2003}, date = {2003-04-01}, journal = {Embo J}, volume = {22}, pages = {1451--60}, abstract = {The human opportunistic pathogen Serratia marcescens is a bacterium with a broad host range, and represents a growing problem for public health. Serratia marcescens kills Caenorhabditis elegans after colonizing the nematode's intestine. We used C.elegans to screen a bank of transposon-induced S.marcescens mutants and isolated 23 clones with an attenuated virulence. Nine of the selected bacterial clones also showed a reduced virulence in an insect model of infection. Of these, three exhibited a reduced cytotoxicity in vitro, and among them one was also markedly attenuated in its virulence in a murine lung infection model. For 21 of the 23 mutants, the transposon insertion site was identified. This revealed that among the genes necessary for full in vivo virulence are those that function in lipopolysaccharide (LPS) biosynthesis, iron uptake and hemolysin production. Using this system we also identified novel conserved virulence factors required for Pseudomonas aeruginosa pathogenicity. This study extends the utility of C.elegans as an in vivo model for the study of bacterial virulence and advances the molecular understanding of S.marcescens pathogenicity.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The human opportunistic pathogen Serratia marcescens is a bacterium with a broad host range, and represents a growing problem for public health. Serratia marcescens kills Caenorhabditis elegans after colonizing the nematode's intestine. We used C.elegans to screen a bank of transposon-induced S.marcescens mutants and isolated 23 clones with an attenuated virulence. Nine of the selected bacterial clones also showed a reduced virulence in an insect model of infection. Of these, three exhibited a reduced cytotoxicity in vitro, and among them one was also markedly attenuated in its virulence in a murine lung infection model. For 21 of the 23 mutants, the transposon insertion site was identified. This revealed that among the genes necessary for full in vivo virulence are those that function in lipopolysaccharide (LPS) biosynthesis, iron uptake and hemolysin production. Using this system we also identified novel conserved virulence factors required for Pseudomonas aeruginosa pathogenicity. This study extends the utility of C.elegans as an in vivo model for the study of bacterial virulence and advances the molecular understanding of S.marcescens pathogenicity. |
| 138. | Imler, Jean-Luc; Hoffmann, Jules A Toll signaling: the TIReless quest for specificity Article de journal Nature Immunology, 4 (2), p. 105–106, 2003, ISSN: 1529-2908. @article{imler_toll_2003, title = {Toll signaling: the TIReless quest for specificity}, author = { Jean-Luc Imler and Jules A. Hoffmann}, doi = {10.1038/ni0203-105}, issn = {1529-2908}, year = {2003}, date = {2003-02-01}, journal = {Nature Immunology}, volume = {4}, number = {2}, pages = {105--106}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
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Articles de journaux |
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| 137. | Munier, Anne-Isabelle; Doucet, Daniel; Perrodou, Emmanuel; Zachary, Daniel; Meister, Marie; Hoffmann, Jules A; Janeway, Charles A; Lagueux, Marie PVF2, a PDGF/VEGF-like growth factor, induces hemocyte proliferation in Drosophila larvae Article de journal EMBO Rep., 3 (12), p. 1195–1200, 2002, ISSN: 1469-221X. @article{munier_pvf2_2002, title = {PVF2, a PDGF/VEGF-like growth factor, induces hemocyte proliferation in Drosophila larvae}, author = { Anne-Isabelle Munier and Daniel Doucet and Emmanuel Perrodou and Daniel Zachary and Marie Meister and Jules A. Hoffmann and Charles A. Janeway and Marie Lagueux}, doi = {10.1093/embo-reports/kvf242}, issn = {1469-221X}, year = {2002}, date = {2002-12-01}, journal = {EMBO Rep.}, volume = {3}, number = {12}, pages = {1195--1200}, abstract = {Blood cells play a crucial role in both morphogenetic and immunological processes in Drosophila, yet the factors regulating their proliferation remain largely unknown. In order to address this question, we raised antibodies against a tumorous blood cell line and identified an antigenic determinant that marks the surface of prohemocytes and also circulating plasmatocytes in larvae. This antigen was identified as a Drosophila homolog of the mammalian receptor for platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF). The Drosophila receptor controls cell proliferation in vitro. By overexpressing in vivo one of its putative ligands, PVF2, we induced a dramatic increase in circulating hemocytes. These results identify the PDGF/VEGF receptor homolog and one of its ligands as important players in Drosophila hematopoiesis.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Blood cells play a crucial role in both morphogenetic and immunological processes in Drosophila, yet the factors regulating their proliferation remain largely unknown. In order to address this question, we raised antibodies against a tumorous blood cell line and identified an antigenic determinant that marks the surface of prohemocytes and also circulating plasmatocytes in larvae. This antigen was identified as a Drosophila homolog of the mammalian receptor for platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF). The Drosophila receptor controls cell proliferation in vitro. By overexpressing in vivo one of its putative ligands, PVF2, we induced a dramatic increase in circulating hemocytes. These results identify the PDGF/VEGF receptor homolog and one of its ligands as important players in Drosophila hematopoiesis. |
| 136. | Ligoxygakis, Petros; Pelte, Nadège ; Ji, Chuanyi ; Leclerc, Vincent ; Duvic, Bernard ; Belvin, Marcia ; Jiang, Haobo ; Hoffmann, Jules A; Reichhart, Jean-Marc A serpin mutant links Toll activation to melanization in the host defence of Drosophila Article de journal EMBO J., 21 (23), p. 6330–6337, 2002, ISSN: 0261-4189. @article{ligoxygakis_serpin_2002, title = {A serpin mutant links Toll activation to melanization in the host defence of Drosophila}, author = { Petros Ligoxygakis and Nadège Pelte and Chuanyi Ji and Vincent Leclerc and Bernard Duvic and Marcia Belvin and Haobo Jiang and Jules A. Hoffmann and Jean-Marc Reichhart}, issn = {0261-4189}, year = {2002}, date = {2002-12-01}, journal = {EMBO J.}, volume = {21}, number = {23}, pages = {6330--6337}, abstract = {A prominent response during the Drosophila host defence is the induction of proteolytic cascades, some of which lead to localized melanization of pathogen surfaces, while others activate one of the major players in the systemic antimicrobial response, the Toll pathway. Despite the fact that gain-of-function mutations in the Toll receptor gene result in melanization, a clear link between Toll activation and the melanization reaction has not been firmly established. Here, we present evidence for the coordination of hemolymph-borne melanization with activation of the Toll pathway in the Drosophila host defence. The melanization reaction requires Toll pathway activation and depends on the removal of the Drosophila serine protease inhibitor Serpin27A. Flies deficient for this serpin exhibit spontaneous melanization in larvae and adults. Microbial challenge induces its removal from the hemolymph through Toll-dependent transcription of an acute phase immune reaction component.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A prominent response during the Drosophila host defence is the induction of proteolytic cascades, some of which lead to localized melanization of pathogen surfaces, while others activate one of the major players in the systemic antimicrobial response, the Toll pathway. Despite the fact that gain-of-function mutations in the Toll receptor gene result in melanization, a clear link between Toll activation and the melanization reaction has not been firmly established. Here, we present evidence for the coordination of hemolymph-borne melanization with activation of the Toll pathway in the Drosophila host defence. The melanization reaction requires Toll pathway activation and depends on the removal of the Drosophila serine protease inhibitor Serpin27A. Flies deficient for this serpin exhibit spontaneous melanization in larvae and adults. Microbial challenge induces its removal from the hemolymph through Toll-dependent transcription of an acute phase immune reaction component. |
| 135. | Kambris, Zakaria; Hoffmann, Jules A; Imler, Jean-Luc ; Capovilla, Maria Tissue and stage-specific expression of the Tolls in Drosophila embryos Article de journal Gene expression patterns: GEP, 2 (3-4), p. 311–317, 2002, ISSN: 1567-133X. @article{kambris_tissue_2002, title = {Tissue and stage-specific expression of the Tolls in Drosophila embryos}, author = { Zakaria Kambris and Jules A. Hoffmann and Jean-Luc Imler and Maria Capovilla}, issn = {1567-133X}, year = {2002}, date = {2002-12-01}, journal = {Gene expression patterns: GEP}, volume = {2}, number = {3-4}, pages = {311--317}, abstract = {The Drosophila transmembrane receptor Toll plays a key role in specifying the dorsoventral axis of the embryo. At later stages of development, it controls the immune response of the fly to fungal and Gram-positive bacterial infections. The Drosophila genome has a total of nine Toll-like genes, including the previously characterized Toll (Toll-1) and 18-wheeler (Toll-2). Here we describe the embryonic expression patterns of the seven Toll-like genes Toll-3 through Toll-9. We find that these genes have distinct expression domains and that their expression is dynamically changing throughout embryonic development. This complex and tissue-specific regulation of Toll-like gene expression strongly suggests a role in embryonic development for most Drosophila Tolls. The evolving picture on the Toll family members in Drosophila contrasts with that of mammalian Toll-like receptors, which are predominantly expressed in immune responsive cells where their activation occurs via microbial structural determinants.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Drosophila transmembrane receptor Toll plays a key role in specifying the dorsoventral axis of the embryo. At later stages of development, it controls the immune response of the fly to fungal and Gram-positive bacterial infections. The Drosophila genome has a total of nine Toll-like genes, including the previously characterized Toll (Toll-1) and 18-wheeler (Toll-2). Here we describe the embryonic expression patterns of the seven Toll-like genes Toll-3 through Toll-9. We find that these genes have distinct expression domains and that their expression is dynamically changing throughout embryonic development. This complex and tissue-specific regulation of Toll-like gene expression strongly suggests a role in embryonic development for most Drosophila Tolls. The evolving picture on the Toll family members in Drosophila contrasts with that of mammalian Toll-like receptors, which are predominantly expressed in immune responsive cells where their activation occurs via microbial structural determinants. |
| 134. | Duvic, Bernard; Hoffmann, Jules A; Meister, Marie; Royet, Julien Notch signaling controls lineage specification during Drosophila larval hematopoiesis Article de journal Curr. Biol., 12 (22), p. 1923–1927, 2002, ISSN: 0960-9822. @article{duvic_notch_2002, title = {Notch signaling controls lineage specification during Drosophila larval hematopoiesis}, author = { Bernard Duvic and Jules A. Hoffmann and Marie Meister and Julien Royet}, issn = {0960-9822}, year = {2002}, date = {2002-11-01}, journal = {Curr. Biol.}, volume = {12}, number = {22}, pages = {1923--1927}, abstract = {Drosophila larval hemocytes originate from a hematopoietic organ called lymph glands, which are composed of paired lobes located along the dorsal vessel. Two mature blood cell populations are found in the circulating hemolymph: the macrophage-like plasmatocytes, and the crystal cells that contain enzymes of the immune-related melanization process. A third class of cells, called lamellocytes, are normally absent in larvae but differentiate after infection by parasites too large to be phagocytosed. Here we present evidence that the Notch signaling pathway plays an instructive role in the differentiation of crystal cells. Loss-of-function mutations in Notch result in severely decreased crystal cell numbers, whereas overexpression of Notch provokes the differentiation of high numbers of these cells. We demonstrate that, in this process, Serrate, not Delta, is the Notch ligand. In addition, Notch function is necessary for lamellocyte proliferation upon parasitization, although Notch overexpression does not result in lamellocyte production. Finally, Notch does not appear to play a role in the differentiation of the plasmatocyte lineage. This study underlines the existence of parallels in the genetic control of hematopoiesis in Drosophila and in mammals.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Drosophila larval hemocytes originate from a hematopoietic organ called lymph glands, which are composed of paired lobes located along the dorsal vessel. Two mature blood cell populations are found in the circulating hemolymph: the macrophage-like plasmatocytes, and the crystal cells that contain enzymes of the immune-related melanization process. A third class of cells, called lamellocytes, are normally absent in larvae but differentiate after infection by parasites too large to be phagocytosed. Here we present evidence that the Notch signaling pathway plays an instructive role in the differentiation of crystal cells. Loss-of-function mutations in Notch result in severely decreased crystal cell numbers, whereas overexpression of Notch provokes the differentiation of high numbers of these cells. We demonstrate that, in this process, Serrate, not Delta, is the Notch ligand. In addition, Notch function is necessary for lamellocyte proliferation upon parasitization, although Notch overexpression does not result in lamellocyte production. Finally, Notch does not appear to play a role in the differentiation of the plasmatocyte lineage. This study underlines the existence of parallels in the genetic control of hematopoiesis in Drosophila and in mammals. |
| 133. | Naitza, Silvia; Rossé, Carine ; Kappler, Christine ; Georgel, Philippe ; Belvin, Marcia ; Gubb, David ; Camonis, Jacques ; Hoffmann, Jules A; Reichhart, Jean-Marc The Drosophila immune defense against gram-negative infection requires the death protein dFADD Article de journal Immunity, 17 (5), p. 575–581, 2002, ISSN: 1074-7613. @article{naitza_drosophila_2002, title = {The Drosophila immune defense against gram-negative infection requires the death protein dFADD}, author = { Silvia Naitza and Carine Rossé and Christine Kappler and Philippe Georgel and Marcia Belvin and David Gubb and Jacques Camonis and Jules A. Hoffmann and Jean-Marc Reichhart}, issn = {1074-7613}, year = {2002}, date = {2002-11-01}, journal = {Immunity}, volume = {17}, number = {5}, pages = {575--581}, abstract = {Drosophila responds to Gram-negative infections by mounting an immune response that depends on components of the IMD pathway. We recently showed that imd encodes a protein with a death domain with high similarity to that of mammalian RIP. Using a two-hybrid screen in yeast, we have isolated the death protein dFADD as a molecule that associates with IMD. Our data show that loss of dFADD function renders flies highly susceptible to Gram-negative infections without affecting resistance to Gram-positive bacteria. By genetic analysis we show that dFADD acts downstream of IMD in the pathway that controls inducibility of the antibacterial peptide genes.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Drosophila responds to Gram-negative infections by mounting an immune response that depends on components of the IMD pathway. We recently showed that imd encodes a protein with a death domain with high similarity to that of mammalian RIP. Using a two-hybrid screen in yeast, we have isolated the death protein dFADD as a molecule that associates with IMD. Our data show that loss of dFADD function renders flies highly susceptible to Gram-negative infections without affecting resistance to Gram-positive bacteria. By genetic analysis we show that dFADD acts downstream of IMD in the pathway that controls inducibility of the antibacterial peptide genes. |
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