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2014
Imler Jean-Luc
Overview of Drosophila immunity: a historical perspective Journal Article
In: Developmental and Comparative Immunology, vol. 42, no. 1, pp. 3–15, 2014, ISSN: 1879-0089.
Abstract | Links | BibTeX | Tags: Allergy and Immunology, Animal, Animals, Antimicrobial Cationic Peptides, Antimicrobial peptides, history, Humans, IMD pathway, imler, Immunity, Innate, innate immunity, M3i, Models, Pattern recognition receptors, Signal Transduction, Toll-Like Receptors
@article{imler_overview_2014,
title = {Overview of Drosophila immunity: a historical perspective},
author = {Jean-Luc Imler},
doi = {10.1016/j.dci.2013.08.018},
issn = {1879-0089},
year = {2014},
date = {2014-01-01},
journal = {Developmental and Comparative Immunology},
volume = {42},
number = {1},
pages = {3--15},
abstract = {The functional analysis of genes from the model organism Drosophila melanogaster has provided invaluable information for many cellular and developmental or physiological processes, including immunity. The best-understood aspect of Drosophila immunity is the inducible humoral response, first recognized in 1972. This pioneering work led to a remarkable series of findings over the next 30 years, ranging from the identification and characterization of the antimicrobial peptides produced, to the deciphering of the signalling pathways activating the genes that encode them and, ultimately, to the discovery of the receptors sensing infection. These studies on an insect model coincided with a revival of the field of innate immunity, and had an unanticipated impact on the biomedical field.},
keywords = {Allergy and Immunology, Animal, Animals, Antimicrobial Cationic Peptides, Antimicrobial peptides, history, Humans, IMD pathway, imler, Immunity, Innate, innate immunity, M3i, Models, Pattern recognition receptors, Signal Transduction, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
The functional analysis of genes from the model organism Drosophila melanogaster has provided invaluable information for many cellular and developmental or physiological processes, including immunity. The best-understood aspect of Drosophila immunity is the inducible humoral response, first recognized in 1972. This pioneering work led to a remarkable series of findings over the next 30 years, ranging from the identification and characterization of the antimicrobial peptides produced, to the deciphering of the signalling pathways activating the genes that encode them and, ultimately, to the discovery of the receptors sensing infection. These studies on an insect model coincided with a revival of the field of innate immunity, and had an unanticipated impact on the biomedical field.
2013
Quintin Jessica, Asmar Joelle, Matskevich Alexey A, Lafarge Marie-Céline, Ferrandon Dominique
The Drosophila Toll pathway controls but does not clear Candida glabrata infections Journal Article
In: J. Immunol., vol. 190, no. 6, pp. 2818–2827, 2013, ISSN: 1550-6606.
Abstract | Links | BibTeX | Tags: Adaptor Proteins, Animal, Animals, Antigens, Candida glabrata, Candidiasis, Cells, Cultured, Differentiation, Disease Models, ferrandon, Immunologic, M3i, Phagocytosis, Receptors, Signal Transducing, Signal Transduction, Toll-Like Receptors, Virulence
@article{quintin_drosophila_2013b,
title = {The Drosophila Toll pathway controls but does not clear Candida glabrata infections},
author = {Jessica Quintin and Joelle Asmar and Alexey A Matskevich and Marie-Céline Lafarge and Dominique Ferrandon},
doi = {10.4049/jimmunol.1201861},
issn = {1550-6606},
year = {2013},
date = {2013-03-01},
journal = {J. Immunol.},
volume = {190},
number = {6},
pages = {2818--2827},
abstract = {The pathogenicity of Candida glabrata to patients remains poorly understood for lack of convenient animal models to screen large numbers of mutants for altered virulence. In this study, we explore the minihost model Drosophila melanogaster from the dual perspective of host and pathogen. As in vertebrates, wild-type flies contain C. glabrata systemic infections yet are unable to kill the injected yeasts. As for other fungal infections in Drosophila, the Toll pathway restrains C. glabrata proliferation. Persistent C. glabrata yeasts in wild-type flies do not appear to be able to take shelter in hemocytes from the action of the Toll pathway, the effectors of which remain to be identified. Toll pathway mutant flies succumb to injected C. glabrata. In this immunosuppressed background, cellular defenses provide a residual level of protection. Although both the Gram-negative binding protein 3 pattern recognition receptor and the Persephone protease-dependent detection pathway are required for Toll pathway activation by C. glabrata, only GNBP3, and not psh mutants, are susceptible to the infection. Both Candida albicans and C. glabrata are restrained by the Toll pathway, yet the comparative study of phenoloxidase activation reveals a differential activity of the Toll pathway against these two fungal pathogens. Finally, we establish that the high-osmolarity glycerol pathway and yapsins are required for virulence of C. glabrata in this model. Unexpectedly, yapsins do not appear to be required to counteract the cellular immune response but are needed for the colonization of the wild-type host.},
keywords = {Adaptor Proteins, Animal, Animals, Antigens, Candida glabrata, Candidiasis, Cells, Cultured, Differentiation, Disease Models, ferrandon, Immunologic, M3i, Phagocytosis, Receptors, Signal Transducing, Signal Transduction, Toll-Like Receptors, Virulence},
pubstate = {published},
tppubtype = {article}
}
The pathogenicity of Candida glabrata to patients remains poorly understood for lack of convenient animal models to screen large numbers of mutants for altered virulence. In this study, we explore the minihost model Drosophila melanogaster from the dual perspective of host and pathogen. As in vertebrates, wild-type flies contain C. glabrata systemic infections yet are unable to kill the injected yeasts. As for other fungal infections in Drosophila, the Toll pathway restrains C. glabrata proliferation. Persistent C. glabrata yeasts in wild-type flies do not appear to be able to take shelter in hemocytes from the action of the Toll pathway, the effectors of which remain to be identified. Toll pathway mutant flies succumb to injected C. glabrata. In this immunosuppressed background, cellular defenses provide a residual level of protection. Although both the Gram-negative binding protein 3 pattern recognition receptor and the Persephone protease-dependent detection pathway are required for Toll pathway activation by C. glabrata, only GNBP3, and not psh mutants, are susceptible to the infection. Both Candida albicans and C. glabrata are restrained by the Toll pathway, yet the comparative study of phenoloxidase activation reveals a differential activity of the Toll pathway against these two fungal pathogens. Finally, we establish that the high-osmolarity glycerol pathway and yapsins are required for virulence of C. glabrata in this model. Unexpectedly, yapsins do not appear to be required to counteract the cellular immune response but are needed for the colonization of the wild-type host.
Ayyaz Arshad, Giammarinaro Philippe, Liégeois Samuel, Lestradet Matthieu, Ferrandon Dominique
In: Immunobiology, vol. 218, no. 4, pp. 635–644, 2013, ISSN: 1878-3279.
Abstract | Links | BibTeX | Tags: Adaptor Proteins, Animal, Animals, Antigens, Differentiation, Disease Models, ferrandon, Immunity, Immunologic, Innate, Intestinal Diseases, M3i, Mucosal, Mutation, Receptors, Signal Transducing, Staphylococcal Infections, Staphylococcus, Starvation, Toll-Like Receptors
@article{ayyaz_negative_2013b,
title = {A negative role for MyD88 in the resistance to starvation as revealed in an intestinal infection of Drosophila melanogaster with the Gram-positive bacterium Staphylococcus xylosus},
author = {Arshad Ayyaz and Philippe Giammarinaro and Samuel Liégeois and Matthieu Lestradet and Dominique Ferrandon},
doi = {10.1016/j.imbio.2012.07.027},
issn = {1878-3279},
year = {2013},
date = {2013-01-01},
journal = {Immunobiology},
volume = {218},
number = {4},
pages = {635--644},
abstract = {Drosophila melanogaster is a useful model to investigate mucosal immunity. The immune response to intestinal infections is mediated partly by the Immune deficiency (IMD) pathway, which only gets activated by a type of peptidoglycan lacking in several medically important Gram-positive bacterial species such as Staphylococcus. Thus, the intestinal host defense against such bacterial strains remains poorly known. Here, we have used Staphylococcus xylosus to develop a model of intestinal infections by Gram-positive bacteria. S. xylosus behaves as an opportunistic pathogen in a septic injury model, being able to kill only flies immunodeficient either for the Toll pathway or the cellular response. When ingested, it is controlled by IMD-independent host intestinal defenses, yet flies eventually die. Having excluded an overreaction of the immune response and the action of toxins, we find that flies actually succumb to starvation, likely as a result of a competition for sucrose between the bacteria and the flies. Fat stores of wild-type flies are severely reduced within a day, a period when sucrose is not yet exhausted in the feeding solution. Interestingly, the Toll pathway mutant MyD88 is more resistant to the ingestion of S. xylosus and to starvation than wild-type flies. MyD88 flies do not rapidly deplete their fat stores when starved, in contrast to wild-type flies. Thus, we have uncovered a novel function of MyD88 in the regulation of metabolism that appears to be independent of its known roles in immunity and development.},
keywords = {Adaptor Proteins, Animal, Animals, Antigens, Differentiation, Disease Models, ferrandon, Immunity, Immunologic, Innate, Intestinal Diseases, M3i, Mucosal, Mutation, Receptors, Signal Transducing, Staphylococcal Infections, Staphylococcus, Starvation, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Drosophila melanogaster is a useful model to investigate mucosal immunity. The immune response to intestinal infections is mediated partly by the Immune deficiency (IMD) pathway, which only gets activated by a type of peptidoglycan lacking in several medically important Gram-positive bacterial species such as Staphylococcus. Thus, the intestinal host defense against such bacterial strains remains poorly known. Here, we have used Staphylococcus xylosus to develop a model of intestinal infections by Gram-positive bacteria. S. xylosus behaves as an opportunistic pathogen in a septic injury model, being able to kill only flies immunodeficient either for the Toll pathway or the cellular response. When ingested, it is controlled by IMD-independent host intestinal defenses, yet flies eventually die. Having excluded an overreaction of the immune response and the action of toxins, we find that flies actually succumb to starvation, likely as a result of a competition for sucrose between the bacteria and the flies. Fat stores of wild-type flies are severely reduced within a day, a period when sucrose is not yet exhausted in the feeding solution. Interestingly, the Toll pathway mutant MyD88 is more resistant to the ingestion of S. xylosus and to starvation than wild-type flies. MyD88 flies do not rapidly deplete their fat stores when starved, in contrast to wild-type flies. Thus, we have uncovered a novel function of MyD88 in the regulation of metabolism that appears to be independent of its known roles in immunity and development.
2012
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 Journal Article
In: J. Immunol., vol. 188, no. 11, pp. 5210–5220, 2012, ISSN: 1550-6606.
Abstract | BibTeX | Tags: Animals, Antifungal Agents, Developmental, DNA-Binding Proteins, Gene Expression Regulation, history, hoffmann, M3i, Multigene Family, Mycoses, Phosphoproteins, reichhart, Toll-Like Receptors
@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 = {Animals, Antifungal Agents, Developmental, DNA-Binding Proteins, Gene Expression Regulation, history, hoffmann, M3i, Multigene Family, Mycoses, Phosphoproteins, reichhart, Toll-Like Receptors},
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.
2011
Chtarbanova Stanislava, Imler Jean-Luc
Microbial sensing by Toll receptors: a historical perspective Journal Article
In: Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 8, pp. 1734–1738, 2011, ISSN: 1524-4636.
Abstract | Links | BibTeX | Tags: Animals, Cardiovascular Diseases, history, Host-Pathogen Interactions, Humans, imler, Immunity, Innate, M3i, Macrophages, Toll-Like Receptors
@article{chtarbanova_microbial_2011,
title = {Microbial sensing by Toll receptors: a historical perspective},
author = {Stanislava Chtarbanova and Jean-Luc Imler},
doi = {10.1161/ATVBAHA.108.179523},
issn = {1524-4636},
year = {2011},
date = {2011-08-01},
journal = {Arteriosclerosis, Thrombosis, and Vascular Biology},
volume = {31},
number = {8},
pages = {1734--1738},
abstract = {The family of Toll-like receptors plays an essential role in the induction of the immune response. These receptors sense the presence of microbial ligands and activate the nuclear factor-κB transcription factor. We review the key studies that led from the formulation of the concept of pattern recognition receptors to the characterization of Toll-like receptors, insisting on the important role played by the model organism Drosophila melanogaster and on the increasing evidence connecting these receptors to cardiovascular disease.},
keywords = {Animals, Cardiovascular Diseases, history, Host-Pathogen Interactions, Humans, imler, Immunity, Innate, M3i, Macrophages, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
The family of Toll-like receptors plays an essential role in the induction of the immune response. These receptors sense the presence of microbial ligands and activate the nuclear factor-κB transcription factor. We review the key studies that led from the formulation of the concept of pattern recognition receptors to the characterization of Toll-like receptors, insisting on the important role played by the model organism Drosophila melanogaster and on the increasing evidence connecting these receptors to cardiovascular disease.
Kellenberger Christine, Leone Philippe, Coquet Laurent, Jouenne Thierry, Reichhart Jean-Marc, Roussel Alain
Structure-function analysis of grass clip serine protease involved in Drosophila Toll pathway activation Journal Article
In: J. Biol. Chem., vol. 286, no. 14, pp. 12300–12307, 2011, ISSN: 1083-351X.
Abstract | Links | BibTeX | Tags: Animals, Catalytic Domain, Cell Line, M3i, reichhart, Serine Proteases, Signal Transduction, Structure-Activity Relationship, Toll-Like Receptors
@article{kellenberger_structure-function_2011,
title = {Structure-function analysis of grass clip serine protease involved in Drosophila Toll pathway activation},
author = {Christine Kellenberger and Philippe Leone and Laurent Coquet and Thierry Jouenne and Jean-Marc Reichhart and Alain Roussel},
doi = {10.1074/jbc.M110.182741},
issn = {1083-351X},
year = {2011},
date = {2011-04-01},
journal = {J. Biol. Chem.},
volume = {286},
number = {14},
pages = {12300--12307},
abstract = {Grass is a clip domain serine protease (SP) involved in a proteolytic cascade triggering the Toll pathway activation of Drosophila during an immune response. Epistasic studies position it downstream of the apical protease ModSP and upstream of the terminal protease Spaetzle-processing enzyme. Here, we report the crystal structure of Grass zymogen. We found that Grass displays a rather deep active site cleft comparable with that of proteases of coagulation and complement cascades. A key distinctive feature is the presence of an additional loop (75-loop) in the proximity of the activation site localized on a protruding loop. All biochemical attempts to hydrolyze the activation site of Grass failed, strongly suggesting restricted access to this region. The 75-loop is thus proposed to constitute an original mechanism to prevent spontaneous activation. A comparison of Grass with clip serine proteases of known function involved in analogous proteolytic cascades allowed us to define two groups, according to the presence of the 75-loop and the conformation of the clip domain. One group (devoid of the 75-loop) contains penultimate proteases whereas the other contains terminal proteases. Using this classification, Grass appears to be a terminal protease. This result is evaluated according to the genetic data documenting Grass function.},
keywords = {Animals, Catalytic Domain, Cell Line, M3i, reichhart, Serine Proteases, Signal Transduction, Structure-Activity Relationship, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Grass is a clip domain serine protease (SP) involved in a proteolytic cascade triggering the Toll pathway activation of Drosophila during an immune response. Epistasic studies position it downstream of the apical protease ModSP and upstream of the terminal protease Spaetzle-processing enzyme. Here, we report the crystal structure of Grass zymogen. We found that Grass displays a rather deep active site cleft comparable with that of proteases of coagulation and complement cascades. A key distinctive feature is the presence of an additional loop (75-loop) in the proximity of the activation site localized on a protruding loop. All biochemical attempts to hydrolyze the activation site of Grass failed, strongly suggesting restricted access to this region. The 75-loop is thus proposed to constitute an original mechanism to prevent spontaneous activation. A comparison of Grass with clip serine proteases of known function involved in analogous proteolytic cascades allowed us to define two groups, according to the presence of the 75-loop and the conformation of the clip domain. One group (devoid of the 75-loop) contains penultimate proteases whereas the other contains terminal proteases. Using this classification, Grass appears to be a terminal protease. This result is evaluated according to the genetic data documenting Grass function.
2010
Matskevich Alexey A, Quintin Jessica, Ferrandon Dominique
The Drosophila PRR GNBP3 assembles effector complexes involved in antifungal defenses independently of its Toll-pathway activation function Journal Article
In: Eur. J. Immunol., vol. 40, no. 5, pp. 1244–1254, 2010, ISSN: 1521-4141.
Abstract | Links | BibTeX | Tags: Agglutination, Animals, Beauveria, Beauveria/immunology, Candida albicans, Candida albicans/immunology, Carrier Proteins, Carrier Proteins/*immunology/pharmacology, Drosophila melanogaster/*immunology/microbiology, Drosophila Proteins/*immunology/pharmacology/physiology, Enzyme Activation, ferrandon, Fungal, Fungi, Fungi/*immunology, Hemolymph, Hemolymph/immunology, M3i, Melanins, Melanins/*physiology, Monophenol Monooxygenase, Monophenol Monooxygenase/physiology, Multiprotein Complexes, Multiprotein Complexes/physiology, Recombinant Fusion Proteins, Recombinant Fusion Proteins/pharmacology, Serpins, Serpins/physiology, Spores, Toll-Like Receptors, Toll-Like Receptors/immunology
@article{matskevich_drosophila_2010b,
title = {The Drosophila PRR GNBP3 assembles effector complexes involved in antifungal defenses independently of its Toll-pathway activation function},
author = {Alexey A Matskevich and Jessica Quintin and Dominique Ferrandon},
doi = {10.1002/eji.200940164},
issn = {1521-4141},
year = {2010},
date = {2010-05-01},
journal = {Eur. J. Immunol.},
volume = {40},
number = {5},
pages = {1244--1254},
abstract = {The Drosophila Toll-signaling pathway controls the systemic antifungal host response. Gram-negative binding protein 3 (GNBP3), a member of the beta-glucan recognition protein family senses fungal infections and activates this pathway. A second detection system perceives the activity of proteolytic fungal virulence factors and redundantly activates Toll. GNBP3(hades) mutant flies succumb more rapidly to Candida albicans and to entomopathogenic fungal infections than WT flies, despite normal triggering of the Toll pathway via the virulence detection system. These observations suggest that GNBP3 triggers antifungal defenses that are not dependent on activation of the Toll pathway. Here, we show that GNBP3 agglutinates fungal cells. Furthermore, it can activate melanization in a Toll-independent manner. Melanization is likely to be an essential defense against some fungal infections given that the entomopathogenic fungus Beauveria bassiana inhibits the activity of the main melanization enzymes, the phenol oxidases. Finally, we show that GNBP3 assembles "attack complexes", which comprise phenoloxidase and the necrotic serpin. We propose that Drosophila GNBP3 targets fungi immediately at the inception of the infection by bringing effector molecules in direct contact with the invading microorganisms.},
keywords = {Agglutination, Animals, Beauveria, Beauveria/immunology, Candida albicans, Candida albicans/immunology, Carrier Proteins, Carrier Proteins/*immunology/pharmacology, Drosophila melanogaster/*immunology/microbiology, Drosophila Proteins/*immunology/pharmacology/physiology, Enzyme Activation, ferrandon, Fungal, Fungi, Fungi/*immunology, Hemolymph, Hemolymph/immunology, M3i, Melanins, Melanins/*physiology, Monophenol Monooxygenase, Monophenol Monooxygenase/physiology, Multiprotein Complexes, Multiprotein Complexes/physiology, Recombinant Fusion Proteins, Recombinant Fusion Proteins/pharmacology, Serpins, Serpins/physiology, Spores, Toll-Like Receptors, Toll-Like Receptors/immunology},
pubstate = {published},
tppubtype = {article}
}
The Drosophila Toll-signaling pathway controls the systemic antifungal host response. Gram-negative binding protein 3 (GNBP3), a member of the beta-glucan recognition protein family senses fungal infections and activates this pathway. A second detection system perceives the activity of proteolytic fungal virulence factors and redundantly activates Toll. GNBP3(hades) mutant flies succumb more rapidly to Candida albicans and to entomopathogenic fungal infections than WT flies, despite normal triggering of the Toll pathway via the virulence detection system. These observations suggest that GNBP3 triggers antifungal defenses that are not dependent on activation of the Toll pathway. Here, we show that GNBP3 agglutinates fungal cells. Furthermore, it can activate melanization in a Toll-independent manner. Melanization is likely to be an essential defense against some fungal infections given that the entomopathogenic fungus Beauveria bassiana inhibits the activity of the main melanization enzymes, the phenol oxidases. Finally, we show that GNBP3 assembles "attack complexes", which comprise phenoloxidase and the necrotic serpin. We propose that Drosophila GNBP3 targets fungi immediately at the inception of the infection by bringing effector molecules in direct contact with the invading microorganisms.
2009
Shia Alice K H, Glittenberg Marcus, Thompson Gavin, Weber Alexander N R, Reichhart Jean-Marc, Ligoxygakis Petros
Toll-dependent antimicrobial responses in Drosophila larval fat body require Spätzle secreted by haemocytes Journal Article
In: J. Cell. Sci., vol. 122, no. Pt 24, pp. 4505–4515, 2009, ISSN: 1477-9137.
Abstract | Links | BibTeX | Tags: Animals, Enterococcus faecalis, Escherichia coli, Fat Body, Hemocytes, Larva, M3i, reichhart, Toll-Like Receptors
@article{shia_toll-dependent_2009,
title = {Toll-dependent antimicrobial responses in Drosophila larval fat body require Spätzle secreted by haemocytes},
author = {Alice K H Shia and Marcus Glittenberg and Gavin Thompson and Alexander N R Weber and Jean-Marc Reichhart and Petros Ligoxygakis},
doi = {10.1242/jcs.049155},
issn = {1477-9137},
year = {2009},
date = {2009-12-01},
journal = {J. Cell. Sci.},
volume = {122},
number = {Pt 24},
pages = {4505--4515},
abstract = {In Drosophila, the humoral response characterised by the synthesis of antimicrobial peptides (AMPs) in the fat body (the equivalent of the mammalian liver) and the cellular response mediated by haemocytes (blood cells) engaged in phagocytosis represent two major reactions that counter pathogens. Although considerable analysis has permitted the elucidation of mechanisms pertaining to the two responses individually, the mechanism of their coordination has been unclear. To characterise the signals with which infection might be communicated between blood cells and fat body, we ablated circulating haemocytes and defined the parameters of AMP gene activation in larvae. We found that targeted ablation of blood cells influenced the levels of AMP gene expression in the fat body following both septic injury and oral infection. Expression of the AMP gene drosomycin (a Toll target) was blocked when expression of the Toll ligand Spätzle was knocked down in haemocytes. These results show that in larvae, integration of the two responses in a systemic reaction depend on the production of a cytokine (spz), a process that strongly parallels the mammalian immune response.},
keywords = {Animals, Enterococcus faecalis, Escherichia coli, Fat Body, Hemocytes, Larva, M3i, reichhart, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
In Drosophila, the humoral response characterised by the synthesis of antimicrobial peptides (AMPs) in the fat body (the equivalent of the mammalian liver) and the cellular response mediated by haemocytes (blood cells) engaged in phagocytosis represent two major reactions that counter pathogens. Although considerable analysis has permitted the elucidation of mechanisms pertaining to the two responses individually, the mechanism of their coordination has been unclear. To characterise the signals with which infection might be communicated between blood cells and fat body, we ablated circulating haemocytes and defined the parameters of AMP gene activation in larvae. We found that targeted ablation of blood cells influenced the levels of AMP gene expression in the fat body following both septic injury and oral infection. Expression of the AMP gene drosomycin (a Toll target) was blocked when expression of the Toll ligand Spätzle was knocked down in haemocytes. These results show that in larvae, integration of the two responses in a systemic reaction depend on the production of a cytokine (spz), a process that strongly parallels the mammalian immune response.
2008
Chamy L El, Leclerc V, Caldelari I, Reichhart J-M
Sensing of 'danger signals' and pathogen-associated molecular patterns defines binary signaling pathways 'upstream' of Toll Journal Article
In: Nat. Immunol., vol. 9, no. 10, pp. 1165–1170, 2008, ISSN: 1529-2916.
Abstract | Links | BibTeX | Tags: Animals, Fungi, Genetically Modified, Gram-Positive Bacteria, Gram-Positive Bacterial Infections, In Situ Hybridization, M3i, Mycoses, Pattern Recognition, Peptide Hydrolases, Receptors, reichhart, ROMBY, Serine Endopeptidases, Signal Transduction, Toll-Like Receptors, Unité ARN
@article{el_chamy_sensing_2008,
title = {Sensing of 'danger signals' and pathogen-associated molecular patterns defines binary signaling pathways 'upstream' of Toll},
author = {L El Chamy and V Leclerc and I Caldelari and J-M Reichhart},
doi = {10.1038/ni.1643},
issn = {1529-2916},
year = {2008},
date = {2008-10-01},
journal = {Nat. Immunol.},
volume = {9},
number = {10},
pages = {1165--1170},
abstract = {In drosophila, molecular determinants from fungi and Gram-positive bacteria are detected by circulating pattern-recognition receptors. Published findings suggest that such pattern-recognition receptors activate as-yet-unidentified serine-protease cascades that culminate in the cleavage of Spätzle, the endogenous Toll receptor ligand, and trigger the immune response. We demonstrate here that the protease Grass defines a common activation cascade for the detection of fungi and Gram-positive bacteria mediated by pattern-recognition receptors. The serine protease Persephone, shown before to be specific for fungal detection in a cascade activated by secreted fungal proteases, was also required for the sensing of proteases elicited by bacteria in the hemolymph. Hence, Persephone defines a parallel proteolytic cascade activated by 'danger signals' such as abnormal proteolytic activities.},
keywords = {Animals, Fungi, Genetically Modified, Gram-Positive Bacteria, Gram-Positive Bacterial Infections, In Situ Hybridization, M3i, Mycoses, Pattern Recognition, Peptide Hydrolases, Receptors, reichhart, ROMBY, Serine Endopeptidases, Signal Transduction, Toll-Like Receptors, Unité ARN},
pubstate = {published},
tppubtype = {article}
}
In drosophila, molecular determinants from fungi and Gram-positive bacteria are detected by circulating pattern-recognition receptors. Published findings suggest that such pattern-recognition receptors activate as-yet-unidentified serine-protease cascades that culminate in the cleavage of Spätzle, the endogenous Toll receptor ligand, and trigger the immune response. We demonstrate here that the protease Grass defines a common activation cascade for the detection of fungi and Gram-positive bacteria mediated by pattern-recognition receptors. The serine protease Persephone, shown before to be specific for fungal detection in a cascade activated by secreted fungal proteases, was also required for the sensing of proteases elicited by bacteria in the hemolymph. Hence, Persephone defines a parallel proteolytic cascade activated by 'danger signals' such as abnormal proteolytic activities.
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 Journal Article
In: Nat. Immunol., vol. 9, no. 1, pp. 97–104, 2008, ISSN: 1529-2916.
Abstract | Links | BibTeX | Tags: Animals, Cell Line, Embryo, Fibroblasts, hoffmann, Humans, Immunity, Innate, Interleukin-1beta, M3i, Mammalian, Mice, NF-kappa B, Nuclear Proteins, Proteins, reichhart, Signal Transduction, Toll-Like Receptors, transgenic, Tumor Necrosis Factor-alpha
@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 = {Animals, Cell Line, Embryo, Fibroblasts, hoffmann, Humans, Immunity, Innate, Interleukin-1beta, M3i, Mammalian, Mice, NF-kappa B, Nuclear Proteins, Proteins, reichhart, Signal Transduction, Toll-Like Receptors, transgenic, Tumor Necrosis Factor-alpha},
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
Weber Alexander N R, Gangloff Monique, Moncrieffe Martin C, Hyvert Yann, Imler Jean-Luc, Gay Nicholas J
Role of the Spatzle Pro-domain in the generation of an active toll receptor ligand Journal Article
In: The Journal of Biological Chemistry, vol. 282, no. 18, pp. 13522–13531, 2007, ISSN: 0021-9258.
Abstract | Links | BibTeX | Tags: Animals, Cytokines, dimerization, imler, ligands, M3i, Post-Translational, Protein Binding, Protein Processing, Protein Structure, Signal Transduction, Tertiary, Toll-Like Receptors
@article{weber_role_2007,
title = {Role of the Spatzle Pro-domain in the generation of an active toll receptor ligand},
author = {Alexander N R Weber and Monique Gangloff and Martin C Moncrieffe and Yann Hyvert and Jean-Luc Imler and Nicholas J Gay},
doi = {10.1074/jbc.M700068200},
issn = {0021-9258},
year = {2007},
date = {2007-05-01},
journal = {The Journal of Biological Chemistry},
volume = {282},
number = {18},
pages = {13522--13531},
abstract = {The cytokine Spätzle is the ligand for Drosophila Toll, the prototype of an important family of membrane receptors that function in embryonic patterning and innate immunity. A dimeric precursor of Spätzle is processed by an endoprotease to produce a form (C-106) that cross-links Toll receptor ectodomains and establishes signaling. Here we show that before processing the pro-domain of Spätzle is required for correct biosynthesis and secretion. We mapped two loss-of-function mutations of Spätzle to a discrete site in the pro-domain and showed that the phenotype arises because of a defect in biosynthesis rather than signaling. We also report that the pro-domain and C-106 remain associated after cleavage and that this processed complex signals with the same characteristics as the C-terminal fragment. These results suggest that before activation the determinants on C-106 that bind specifically to Toll are sequestered by the pro-domain and that proteolytic processing causes conformational rearrangements that expose these determinants and enables binding to Toll. Furthermore, we show that the pro-domain is released when the Toll extracellular domain binds to the complex, a finding that has implications for the generation of a signaling-competent Toll dimer.},
keywords = {Animals, Cytokines, dimerization, imler, ligands, M3i, Post-Translational, Protein Binding, Protein Processing, Protein Structure, Signal Transduction, Tertiary, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
The cytokine Spätzle is the ligand for Drosophila Toll, the prototype of an important family of membrane receptors that function in embryonic patterning and innate immunity. A dimeric precursor of Spätzle is processed by an endoprotease to produce a form (C-106) that cross-links Toll receptor ectodomains and establishes signaling. Here we show that before processing the pro-domain of Spätzle is required for correct biosynthesis and secretion. We mapped two loss-of-function mutations of Spätzle to a discrete site in the pro-domain and showed that the phenotype arises because of a defect in biosynthesis rather than signaling. We also report that the pro-domain and C-106 remain associated after cleavage and that this processed complex signals with the same characteristics as the C-terminal fragment. These results suggest that before activation the determinants on C-106 that bind specifically to Toll are sequestered by the pro-domain and that proteolytic processing causes conformational rearrangements that expose these determinants and enables binding to Toll. Furthermore, we show that the pro-domain is released when the Toll extracellular domain binds to the complex, a finding that has implications for the generation of a signaling-competent Toll dimer.
2006
Flacher Vincent, Bouschbacher Marielle, Verronèse Estelle, Massacrier Catherine, Sisirak Vanja, Berthier-Vergnes Odile, de Saint-Vis Blandine, Caux Christophe, Dezutter-Dambuyant Colette, Lebecque Serge, Valladeau Jenny
Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria Journal Article
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 177, no. 11, pp. 7959–7967, 2006, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: bacteria, Double-Stranded, Gram-Positive Bacteria, Human, Humans, Interleukin-6, Interleukin-8, Langerhans Cells, Reverse Transcriptase Polymerase Chain Reaction, RNA, Skin, Team-Mueller, TLR4, TLR7, Toll-Like Receptors, Tumor Necrosis Factor-alpha, viruses
@article{flacher_human_2006,
title = {Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria},
author = {Vincent Flacher and Marielle Bouschbacher and Estelle Verronèse and Catherine Massacrier and Vanja Sisirak and Odile Berthier-Vergnes and Blandine de Saint-Vis and Christophe Caux and Colette Dezutter-Dambuyant and Serge Lebecque and Jenny Valladeau},
doi = {10.4049/jimmunol.177.11.7959},
issn = {0022-1767},
year = {2006},
date = {2006-12-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {177},
number = {11},
pages = {7959--7967},
abstract = {Dendritic cells (DC) are APCs essential for the development of primary immune responses. In pluristratified epithelia, Langerhans cells (LC) are a critical subset of DC which take up Ags and migrate toward lymph nodes upon inflammatory stimuli. TLR allow detection of pathogen-associated molecular patterns (PAMP) by different DC subsets. The repertoire of TLR expressed by human LC is uncharacterized and their ability to directly respond to PAMP has not been systematically investigated. In this study, we show for the first time that freshly purified LC from human skin express mRNA encoding TLR1, TLR2, TLR3, TLR5, TLR6 and TLR10. In addition, keratinocytes ex vivo display TLR1-5, TLR7, and TLR10. Accordingly, highly enriched immature LC efficiently respond to TLR2 agonists peptidoglycan and lipoteichoic acid from Gram-positive bacteria, and to dsRNA which engages TLR3. In contrast, LC do not directly sense TLR7/8 ligands and LPS from Gram-negative bacteria, which signals through TLR4. TLR engagement also results in cytokine production, with marked differences depending on the PAMP detected. TLR2 and TLR3 ligands increase IL-6 and IL-8 production, while dsRNA alone stimulates TNF-alpha release. Strikingly, only peptidoglycan triggers IL-10 secretion, thereby suggesting a specific function in tolerance to commensal Gram-positive bacteria. However, LC do not produce IL-12p70 or type I IFNs. In conclusion, human LC are equipped with TLR that enable direct detection of PAMP from viruses and Gram-positive bacteria, subsequent phenotypic maturation, and differential cytokine production. This implies a significant role for LC in the control of skin immune responses.},
keywords = {bacteria, Double-Stranded, Gram-Positive Bacteria, Human, Humans, Interleukin-6, Interleukin-8, Langerhans Cells, Reverse Transcriptase Polymerase Chain Reaction, RNA, Skin, Team-Mueller, TLR4, TLR7, Toll-Like Receptors, Tumor Necrosis Factor-alpha, viruses},
pubstate = {published},
tppubtype = {article}
}
Dendritic cells (DC) are APCs essential for the development of primary immune responses. In pluristratified epithelia, Langerhans cells (LC) are a critical subset of DC which take up Ags and migrate toward lymph nodes upon inflammatory stimuli. TLR allow detection of pathogen-associated molecular patterns (PAMP) by different DC subsets. The repertoire of TLR expressed by human LC is uncharacterized and their ability to directly respond to PAMP has not been systematically investigated. In this study, we show for the first time that freshly purified LC from human skin express mRNA encoding TLR1, TLR2, TLR3, TLR5, TLR6 and TLR10. In addition, keratinocytes ex vivo display TLR1-5, TLR7, and TLR10. Accordingly, highly enriched immature LC efficiently respond to TLR2 agonists peptidoglycan and lipoteichoic acid from Gram-positive bacteria, and to dsRNA which engages TLR3. In contrast, LC do not directly sense TLR7/8 ligands and LPS from Gram-negative bacteria, which signals through TLR4. TLR engagement also results in cytokine production, with marked differences depending on the PAMP detected. TLR2 and TLR3 ligands increase IL-6 and IL-8 production, while dsRNA alone stimulates TNF-alpha release. Strikingly, only peptidoglycan triggers IL-10 secretion, thereby suggesting a specific function in tolerance to commensal Gram-positive bacteria. However, LC do not produce IL-12p70 or type I IFNs. In conclusion, human LC are equipped with TLR that enable direct detection of PAMP from viruses and Gram-positive bacteria, subsequent phenotypic maturation, and differential cytokine production. This implies a significant role for LC in the control of skin immune responses.
Evans J D, Aronstein K, Chen Y P, Hetru Charles, Imler Jean-Luc, Jiang H, Kanost M, Thompson G J, Zou Z, Hultmark D
Immune pathways and defence mechanisms in honey bees Apis mellifera Journal Article
In: Insect Molecular Biology, vol. 15, no. 5, pp. 645–656, 2006, ISSN: 0962-1075.
Abstract | Links | BibTeX | Tags: Animals, Bees, Carrier Proteins, Genome, imler, Immunity, Insect, Janus Kinases, M3i, Multigene Family, Serine Endopeptidases, Signal Transduction, STAT Transcription Factors, Toll-Like Receptors
@article{evans_immune_2006,
title = {Immune pathways and defence mechanisms in honey bees Apis mellifera},
author = {J D Evans and K Aronstein and Y P Chen and Charles Hetru and Jean-Luc Imler and H Jiang and M Kanost and G J Thompson and Z Zou and D Hultmark},
doi = {10.1111/j.1365-2583.2006.00682.x},
issn = {0962-1075},
year = {2006},
date = {2006-10-01},
journal = {Insect Molecular Biology},
volume = {15},
number = {5},
pages = {645--656},
abstract = {Social insects are able to mount both group-level and individual defences against pathogens. Here we focus on individual defences, by presenting a genome-wide analysis of immunity in a social insect, the honey bee Apis mellifera. We present honey bee models for each of four signalling pathways associated with immunity, identifying plausible orthologues for nearly all predicted pathway members. When compared to the sequenced Drosophila and Anopheles genomes, honey bees possess roughly one-third as many genes in 17 gene families implicated in insect immunity. We suggest that an implied reduction in immune flexibility in bees reflects either the strength of social barriers to disease, or a tendency for bees to be attacked by a limited set of highly coevolved pathogens.},
keywords = {Animals, Bees, Carrier Proteins, Genome, imler, Immunity, Insect, Janus Kinases, M3i, Multigene Family, Serine Endopeptidases, Signal Transduction, STAT Transcription Factors, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Social insects are able to mount both group-level and individual defences against pathogens. Here we focus on individual defences, by presenting a genome-wide analysis of immunity in a social insect, the honey bee Apis mellifera. We present honey bee models for each of four signalling pathways associated with immunity, identifying plausible orthologues for nearly all predicted pathway members. When compared to the sequenced Drosophila and Anopheles genomes, honey bees possess roughly one-third as many genes in 17 gene families implicated in insect immunity. We suggest that an implied reduction in immune flexibility in bees reflects either the strength of social barriers to disease, or a tendency for bees to be attacked by a limited set of highly coevolved pathogens.
Chen Li-Ying, Wang Juinn-Chin, Hyvert Yann, Lin Hui-Ping, Perrimon Norbert, Imler Jean-Luc, Hsu Jui-Chou
Weckle is a zinc finger adaptor of the toll pathway in dorsoventral patterning of the Drosophila embryo Journal Article
In: Current biology: CB, vol. 16, no. 12, pp. 1183–1193, 2006, ISSN: 0960-9822.
Abstract | Links | BibTeX | Tags: Adaptor Proteins, Animals, Antigens, Biological, Body Patterning, Cell Membrane, Differentiation, dimerization, DNA-Binding Proteins, Embryo, Epistasis, Genetic, imler, Immunity, Immunologic, Innate, M3i, Models, Mutation, Nonmammalian, Phenotype, Phosphoproteins, Receptors, Signal Transducing, Toll-Like Receptors, Transcription Factors, Zinc Fingers
@article{chen_weckle_2006,
title = {Weckle is a zinc finger adaptor of the toll pathway in dorsoventral patterning of the Drosophila embryo},
author = {Li-Ying Chen and Juinn-Chin Wang and Yann Hyvert and Hui-Ping Lin and Norbert Perrimon and Jean-Luc Imler and Jui-Chou Hsu},
doi = {10.1016/j.cub.2006.05.050},
issn = {0960-9822},
year = {2006},
date = {2006-06-01},
journal = {Current biology: CB},
volume = {16},
number = {12},
pages = {1183--1193},
abstract = {BACKGROUND: The Drosophila Toll pathway takes part in both establishment of the embryonic dorsoventral axis and induction of the innate immune response in adults. Upon activation by the cytokine Spätzle, Toll interacts with the adaptor proteins DmMyD88 and Tube and the kinase Pelle and triggers degradation of the inhibitor Cactus, thus allowing the nuclear translocation of the transcription factor Dorsal/Dif. weckle (wek) was previously identified as a new dorsal group gene that encodes a putative zinc finger transcription factor. However, its role in the Toll pathway was unknown. RESULTS: Here, we isolated new wek alleles and demonstrated that cactus is epistatic to wek, which in turn is epistatic to Toll. Consistent with this, Wek localizes to the plasma membrane of embryos, independently of Toll signaling. Wek homodimerizes and associates with Toll. Moreover, Wek binds to and localizes DmMyD88 to the plasma membrane. Thus, Wek acts as an adaptor to assemble/stabilize a Toll/Wek/DmMyD88/Tube complex. Remarkably, unlike the DmMyD88/tube/pelle/cactus gene cassette of the Toll pathway, wek plays a minimal role, if any, in the immune defense against Gram-positive bacteria and fungi. CONCLUSIONS: We conclude that Wek is an adaptor to link Toll and DmMyD88 and is required for efficient recruitment of DmMyD88 to Toll. Unexpectedly, wek is dispensable for innate immune response, thus revealing differences in the Toll-mediated activation of Dorsal in the embryo and Dif in the fat body of adult flies.},
keywords = {Adaptor Proteins, Animals, Antigens, Biological, Body Patterning, Cell Membrane, Differentiation, dimerization, DNA-Binding Proteins, Embryo, Epistasis, Genetic, imler, Immunity, Immunologic, Innate, M3i, Models, Mutation, Nonmammalian, Phenotype, Phosphoproteins, Receptors, Signal Transducing, Toll-Like Receptors, Transcription Factors, Zinc Fingers},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The Drosophila Toll pathway takes part in both establishment of the embryonic dorsoventral axis and induction of the innate immune response in adults. Upon activation by the cytokine Spätzle, Toll interacts with the adaptor proteins DmMyD88 and Tube and the kinase Pelle and triggers degradation of the inhibitor Cactus, thus allowing the nuclear translocation of the transcription factor Dorsal/Dif. weckle (wek) was previously identified as a new dorsal group gene that encodes a putative zinc finger transcription factor. However, its role in the Toll pathway was unknown. RESULTS: Here, we isolated new wek alleles and demonstrated that cactus is epistatic to wek, which in turn is epistatic to Toll. Consistent with this, Wek localizes to the plasma membrane of embryos, independently of Toll signaling. Wek homodimerizes and associates with Toll. Moreover, Wek binds to and localizes DmMyD88 to the plasma membrane. Thus, Wek acts as an adaptor to assemble/stabilize a Toll/Wek/DmMyD88/Tube complex. Remarkably, unlike the DmMyD88/tube/pelle/cactus gene cassette of the Toll pathway, wek plays a minimal role, if any, in the immune defense against Gram-positive bacteria and fungi. CONCLUSIONS: We conclude that Wek is an adaptor to link Toll and DmMyD88 and is required for efficient recruitment of DmMyD88 to Toll. Unexpectedly, wek is dispensable for innate immune response, thus revealing differences in the Toll-mediated activation of Dorsal in the embryo and Dif in the fat body of adult flies.
Galiana-Arnoux Delphine, Imler Jean-Luc
Toll-like receptors and innate antiviral immunity Journal Article
In: Tissue Antigens, vol. 67, no. 4, pp. 267–276, 2006, ISSN: 0001-2815.
Abstract | Links | BibTeX | Tags: Animals, Humans, imler, Immunity, Innate, M3i, Signal Transduction, Toll-Like Receptors, Virus Diseases
@article{galiana-arnoux_toll-like_2006,
title = {Toll-like receptors and innate antiviral immunity},
author = {Delphine Galiana-Arnoux and Jean-Luc Imler},
doi = {10.1111/j.1399-0039.2006.00583.x},
issn = {0001-2815},
year = {2006},
date = {2006-01-01},
journal = {Tissue Antigens},
volume = {67},
number = {4},
pages = {267--276},
abstract = {Viral infections are first detected by a set of innate immunity receptors that detect primary infections by pathogens, and trigger a transcriptional response. Among the induced target genes, type I interferons (IFNs) are central to the antiviral response of the host. The receptors and signaling pathways that mediate the strong induction of the synthesis of these cytokines have long remained elusive. In the past few years, Toll-like receptors (TLRs) emerged as important sensors of infections. Several TLRs participate in the recognition of virus infection, interacting in particular with viral nucleic acids. Upon activation, TLRs interact with different cytosolic adapter molecules and activate transcription factors of the nuclear factor-kappaB and IFN regulatory factor families that concur to mediate induction of IFN-alpha/beta and other inflammatory cytokines. In addition to the transmembrane TLRs, cytosolic helicases also detect viral nucleic acids, and trigger type I IFN synthesis.},
keywords = {Animals, Humans, imler, Immunity, Innate, M3i, Signal Transduction, Toll-Like Receptors, Virus Diseases},
pubstate = {published},
tppubtype = {article}
}
Viral infections are first detected by a set of innate immunity receptors that detect primary infections by pathogens, and trigger a transcriptional response. Among the induced target genes, type I interferons (IFNs) are central to the antiviral response of the host. The receptors and signaling pathways that mediate the strong induction of the synthesis of these cytokines have long remained elusive. In the past few years, Toll-like receptors (TLRs) emerged as important sensors of infections. Several TLRs participate in the recognition of virus infection, interacting in particular with viral nucleic acids. Upon activation, TLRs interact with different cytosolic adapter molecules and activate transcription factors of the nuclear factor-kappaB and IFN regulatory factor families that concur to mediate induction of IFN-alpha/beta and other inflammatory cytokines. In addition to the transmembrane TLRs, cytosolic helicases also detect viral nucleic acids, and trigger type I IFN synthesis.
2005
Martinelli Cosimo, Reichhart Jean-Marc
Evolution and integration of innate immune systems from fruit flies to man: lessons and questions Journal Article
In: J. Endotoxin Res., vol. 11, no. 4, pp. 243–248, 2005, ISSN: 0968-0519.
Abstract | Links | BibTeX | Tags: Animals, Biological Evolution, Cell Surface, Forecasting, Humans, Immunity, Immunological, Innate, M3i, Membrane Glycoproteins, Models, Receptors, reichhart, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors
@article{martinelli_evolution_2005,
title = {Evolution and integration of innate immune systems from fruit flies to man: lessons and questions},
author = {Cosimo Martinelli and Jean-Marc Reichhart},
doi = {10.1179/096805105X37411},
issn = {0968-0519},
year = {2005},
date = {2005-01-01},
journal = {J. Endotoxin Res.},
volume = {11},
number = {4},
pages = {243--248},
abstract = {Despite broad differences in morphology, ecology and behavior, the fruit fly Drosophila melanogaster and humans show a remarkably high degree of conservation for many molecular, cellular, and developmental aspects of their biology. During the last decade, similarities have also been discovered in some of the mechanisms regulating their innate immune system. These parallels regard mainly the Toll-like receptor family and the intracellular signaling pathways involved in the control of the immune response. However, if the overall similarities are important, the detailed pathogen recognition mechanisms differ significantly between fly and humans, highlighting a complicated evolutionary history of the metazoan innate defenses. In this review, we will discuss the main similarities and differences between the two types of organisms. We hope that this current knowledge will be used as a starting point for a more comprehensive view of innate immunity within the broad variety of metazoan phyla.},
keywords = {Animals, Biological Evolution, Cell Surface, Forecasting, Humans, Immunity, Immunological, Innate, M3i, Membrane Glycoproteins, Models, Receptors, reichhart, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Despite broad differences in morphology, ecology and behavior, the fruit fly Drosophila melanogaster and humans show a remarkably high degree of conservation for many molecular, cellular, and developmental aspects of their biology. During the last decade, similarities have also been discovered in some of the mechanisms regulating their innate immune system. These parallels regard mainly the Toll-like receptor family and the intracellular signaling pathways involved in the control of the immune response. However, if the overall similarities are important, the detailed pathogen recognition mechanisms differ significantly between fly and humans, highlighting a complicated evolutionary history of the metazoan innate defenses. In this review, we will discuss the main similarities and differences between the two types of organisms. We hope that this current knowledge will be used as a starting point for a more comprehensive view of innate immunity within the broad variety of metazoan phyla.
Weber Alexander N R, Moncrieffe Martin C, Gangloff Monique, Imler Jean-Luc, Gay Nicholas J
Ligand-receptor and receptor-receptor interactions act in concert to activate signaling in the Drosophila toll pathway Journal Article
In: The Journal of Biological Chemistry, vol. 280, no. 24, pp. 22793–22799, 2005, ISSN: 0021-9258.
Abstract | Links | BibTeX | Tags: Amino Acid, Animals, Biophysical Phenomena, Biophysics, Body Patterning, Calorimetry, Cell Line, Cell Surface, Cross-Linking Reagents, Cytokines, dimerization, Electrophoresis, Humans, imler, ligands, Luciferases, M3i, Membrane Glycoproteins, Polyacrylamide Gel, Protein Binding, Protein Structure, Receptors, Recombinant Proteins, Sequence Homology, Signal Transduction, Tertiary, Time Factors, Toll-Like Receptors, Ultracentrifugation
@article{weber_ligand-receptor_2005,
title = {Ligand-receptor and receptor-receptor interactions act in concert to activate signaling in the Drosophila toll pathway},
author = {Alexander N R Weber and Martin C Moncrieffe and Monique Gangloff and Jean-Luc Imler and Nicholas J Gay},
doi = {10.1074/jbc.M502074200},
issn = {0021-9258},
year = {2005},
date = {2005-01-01},
journal = {The Journal of Biological Chemistry},
volume = {280},
number = {24},
pages = {22793--22799},
abstract = {In Drosophila, the signaling pathway mediated by the Toll receptor is critical for the establishment of embryonic dorso-ventral pattern and for innate immune responses to bacterial and fungal pathogens. Toll is activated by high affinity binding of the cytokine Spätzle, a dimeric ligand of the cystine knot family. In vertebrates, a related family of Toll-like receptors play a critical role in innate immune responses. Despite the importance of this family of receptors, little is known about the biochemical events that lead to receptor activation and signaling. Here, we show that Spätzle binds to the N-terminal region of Toll and, using biophysical methods, that the binding is complex. The two binding events that cause formation of the cross-linked complex are non-equivalent: the first Toll ectodomain binds Spätzle with an affinity 3-fold higher than the second molecule suggesting that pathway activation involves negative cooperativity. We further show that the Toll ectodomains are able to form low affinity dimers in solution and that juxtamembrane sequences of Toll are critical for the activation or derepression of the pathway. These results, taken together, suggest a mechanism of signal transduction that requires both ligand-receptor and receptor-receptor interactions.},
keywords = {Amino Acid, Animals, Biophysical Phenomena, Biophysics, Body Patterning, Calorimetry, Cell Line, Cell Surface, Cross-Linking Reagents, Cytokines, dimerization, Electrophoresis, Humans, imler, ligands, Luciferases, M3i, Membrane Glycoproteins, Polyacrylamide Gel, Protein Binding, Protein Structure, Receptors, Recombinant Proteins, Sequence Homology, Signal Transduction, Tertiary, Time Factors, Toll-Like Receptors, Ultracentrifugation},
pubstate = {published},
tppubtype = {article}
}
In Drosophila, the signaling pathway mediated by the Toll receptor is critical for the establishment of embryonic dorso-ventral pattern and for innate immune responses to bacterial and fungal pathogens. Toll is activated by high affinity binding of the cytokine Spätzle, a dimeric ligand of the cystine knot family. In vertebrates, a related family of Toll-like receptors play a critical role in innate immune responses. Despite the importance of this family of receptors, little is known about the biochemical events that lead to receptor activation and signaling. Here, we show that Spätzle binds to the N-terminal region of Toll and, using biophysical methods, that the binding is complex. The two binding events that cause formation of the cross-linked complex are non-equivalent: the first Toll ectodomain binds Spätzle with an affinity 3-fold higher than the second molecule suggesting that pathway activation involves negative cooperativity. We further show that the Toll ectodomains are able to form low affinity dimers in solution and that juxtamembrane sequences of Toll are critical for the activation or derepression of the pathway. These results, taken together, suggest a mechanism of signal transduction that requires both ligand-receptor and receptor-receptor interactions.
2004
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 Journal Article
In: Nat. Immunol., vol. 5, no. 11, pp. 1175–1180, 2004, ISSN: 1529-2908.
Abstract | Links | BibTeX | Tags: Animals, Carrier Proteins, Cell Surface, Gram-Positive Bacteria, Gram-Positive Bacterial Infections, hoffmann, M3i, Mutation, Mycoses, Receptors, Staphylococcus aureus, Toll-Like Receptors
@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 = {Animals, Carrier Proteins, Cell Surface, Gram-Positive Bacteria, Gram-Positive Bacterial Infections, hoffmann, M3i, Mutation, Mycoses, Receptors, Staphylococcus aureus, Toll-Like Receptors},
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.
Leclerc Vincent, Reichhart Jean-Marc
The immune response of Drosophila melanogaster Journal Article
In: Immunol. Rev., vol. 198, pp. 59–71, 2004, ISSN: 0105-2896.
Abstract | BibTeX | Tags: Animals, Cell Surface, Immunity, Immunological, Innate, M3i, Models, Receptors, reichhart, Signal Transduction, Toll-Like Receptors
@article{leclerc_immune_2004,
title = {The immune response of Drosophila melanogaster},
author = {Vincent Leclerc and Jean-Marc Reichhart},
issn = {0105-2896},
year = {2004},
date = {2004-04-01},
journal = {Immunol. Rev.},
volume = {198},
pages = {59--71},
abstract = {The response of the fruit fly Drosophila melanogaster to various microorganism infections relies on a multilayered defense. The epithelia constitute a first and efficient barrier. Innate immunity is activated when microorganisms succeed in entering the body cavity of the fly. Invading microorganisms are killed by the combined action of cellular and humoral processes. They are phagocytosed by specialized blood cells, surrounded by toxic melanin, or lysed by antibacterial peptides secreted into the hemolymph by fat body cells. During the last few years, research has focused on the mechanisms of microbial recognition by various pattern recognition receptors and of the subsequent induction of antimicrobial peptide expression. The cellular arm of the Drosophila innate immune system, which was somehow neglected, now constitutes the new frontier.},
keywords = {Animals, Cell Surface, Immunity, Immunological, Innate, M3i, Models, Receptors, reichhart, Signal Transduction, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
The response of the fruit fly Drosophila melanogaster to various microorganism infections relies on a multilayered defense. The epithelia constitute a first and efficient barrier. Innate immunity is activated when microorganisms succeed in entering the body cavity of the fly. Invading microorganisms are killed by the combined action of cellular and humoral processes. They are phagocytosed by specialized blood cells, surrounded by toxic melanin, or lysed by antibacterial peptides secreted into the hemolymph by fat body cells. During the last few years, research has focused on the mechanisms of microbial recognition by various pattern recognition receptors and of the subsequent induction of antimicrobial peptide expression. The cellular arm of the Drosophila innate immune system, which was somehow neglected, now constitutes the new frontier.
Imler Jean-Luc, Zheng Liangbiao
Biology of Toll receptors: lessons from insects and mammals Journal Article
In: Journal of Leukocyte Biology, vol. 75, no. 1, pp. 18–26, 2004, ISSN: 0741-5400.
Abstract | Links | BibTeX | Tags: Animals, Anopheles, Cell Surface, Humans, imler, M3i, Membrane Glycoproteins, Mice, Phylogeny, Plant Physiological Phenomena, Receptors, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors
@article{imler_biology_2004,
title = {Biology of Toll receptors: lessons from insects and mammals},
author = {Jean-Luc Imler and Liangbiao Zheng},
doi = {10.1189/jlb.0403160},
issn = {0741-5400},
year = {2004},
date = {2004-01-01},
journal = {Journal of Leukocyte Biology},
volume = {75},
number = {1},
pages = {18--26},
abstract = {Toll receptors are type I transmembrane proteins that play important roles in development and immunity in animals. Comparison of the genomes of mouse and human on one side and of the fruitfly Drosophila and the mosquito Anopheles (two dipteran insects) on the other, revealed that the four species possess a similar number of Toll receptors (approximately 10). However, phylogenetic analyses indicate that the families of Toll receptors expanded independently in insects and mammals. We review recent results on these receptors, which point to differences in the activation and signaling between Tolls in insects and Toll-like receptors (TLRs) in mammals. Whereas mammalian TLRs appear to be solely dedicated to host-defense, insect Tolls may be predominantly linked to other functions, probably developmental.},
keywords = {Animals, Anopheles, Cell Surface, Humans, imler, M3i, Membrane Glycoproteins, Mice, Phylogeny, Plant Physiological Phenomena, Receptors, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Toll receptors are type I transmembrane proteins that play important roles in development and immunity in animals. Comparison of the genomes of mouse and human on one side and of the fruitfly Drosophila and the mosquito Anopheles (two dipteran insects) on the other, revealed that the four species possess a similar number of Toll receptors (approximately 10). However, phylogenetic analyses indicate that the families of Toll receptors expanded independently in insects and mammals. We review recent results on these receptors, which point to differences in the activation and signaling between Tolls in insects and Toll-like receptors (TLRs) in mammals. Whereas mammalian TLRs appear to be solely dedicated to host-defense, insect Tolls may be predominantly linked to other functions, probably developmental.
Imler Jean-Luc, Ferrandon Dominique, Royet Julien, Reichhart Jean-Marc, Hetru Charles, Hoffmann Jules A
Toll-dependent and Toll-independent immune responses in Drosophila Journal Article
In: Journal of Endotoxin Research, vol. 10, no. 4, pp. 241–246, 2004, ISSN: 0968-0519.
Abstract | Links | BibTeX | Tags: Acute-Phase Proteins, Animals, Blood Proteins, Cell Surface, ferrandon, hoffmann, imler, Insect Proteins, M3i, Membrane Glycoproteins, Receptors, reichhart, Toll-Like Receptor 5, Toll-Like Receptors, Up-Regulation
@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 = {Acute-Phase Proteins, Animals, Blood Proteins, Cell Surface, ferrandon, hoffmann, imler, Insect Proteins, M3i, Membrane Glycoproteins, Receptors, reichhart, Toll-Like Receptor 5, Toll-Like Receptors, Up-Regulation},
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.
2003
Ligoxygakis Petros, Roth Siegfried, Reichhart Jean-Marc
A serpin regulates dorsal-ventral axis formation in the Drosophila embryo Journal Article
In: Curr. Biol., vol. 13, no. 23, pp. 2097–2102, 2003, ISSN: 0960-9822.
Abstract | BibTeX | Tags: Animals, Body Patterning, Cell Surface, Crosses, Female, Genetic, Immunohistochemistry, M3i, Microinjections, Receptors, reichhart, Serine Proteinase Inhibitors, Serpins, Signal Transduction, Toll-Like Receptors
@article{ligoxygakis_serpin_2003,
title = {A serpin regulates dorsal-ventral axis formation in the Drosophila embryo},
author = {Petros Ligoxygakis and Siegfried Roth and Jean-Marc Reichhart},
issn = {0960-9822},
year = {2003},
date = {2003-12-01},
journal = {Curr. Biol.},
volume = {13},
number = {23},
pages = {2097--2102},
abstract = {Extracellular serine protease cascades have evolved in vertebrates and invertebrates to mediate rapid, local reactions to physiological or pathological cues. The serine protease cascade that triggers the Toll signaling pathway in Drosophila embryogenesis shares several organizational characteristics with those involved in mammalian complement and blood clotting. One of the hallmarks of such cascades is their regulation by serine protease inhibitors (serpins). Serpins act as suicide substrates and are cleaved by their target protease, forming an essentially irreversible 1:1 complex. The biological importance of serpins is highlighted by serpin dysfunction diseases, such as thrombosis caused by a deficiency in antithrombin. Here, we describe how a serpin controls the serine protease cascade, leading to Toll pathway activation. Female flies deficient in Serpin-27A produce embryos that lack dorsal-ventral polarity and show uniform high levels of Toll signaling. Since this serpin has been recently shown to restrain an immune reaction in the blood of Drosophila, it demonstrates that proteolysis can be regulated by the same serpin in different biological contexts.},
keywords = {Animals, Body Patterning, Cell Surface, Crosses, Female, Genetic, Immunohistochemistry, M3i, Microinjections, Receptors, reichhart, Serine Proteinase Inhibitors, Serpins, Signal Transduction, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Extracellular serine protease cascades have evolved in vertebrates and invertebrates to mediate rapid, local reactions to physiological or pathological cues. The serine protease cascade that triggers the Toll signaling pathway in Drosophila embryogenesis shares several organizational characteristics with those involved in mammalian complement and blood clotting. One of the hallmarks of such cascades is their regulation by serine protease inhibitors (serpins). Serpins act as suicide substrates and are cleaved by their target protease, forming an essentially irreversible 1:1 complex. The biological importance of serpins is highlighted by serpin dysfunction diseases, such as thrombosis caused by a deficiency in antithrombin. Here, we describe how a serpin controls the serine protease cascade, leading to Toll pathway activation. Female flies deficient in Serpin-27A produce embryos that lack dorsal-ventral polarity and show uniform high levels of Toll signaling. Since this serpin has been recently shown to restrain an immune reaction in the blood of Drosophila, it demonstrates that proteolysis can be regulated by the same serpin in different biological contexts.
Reichhart Jean-Marc
TLR5 takes aim at bacterial propeller Journal Article
In: Nat. Immunol., vol. 4, no. 12, pp. 1159–1160, 2003, ISSN: 1529-2908.
Links | BibTeX | Tags: Animals, Bacterial Physiological Phenomena, Cell Surface, Flagella, Flagellin, Humans, M3i, Membrane Glycoproteins, Receptors, reichhart, Toll-Like Receptor 5, Toll-Like Receptors
@article{reichhart_tlr5_2003,
title = {TLR5 takes aim at bacterial propeller},
author = {Jean-Marc Reichhart},
doi = {10.1038/ni1203-1159},
issn = {1529-2908},
year = {2003},
date = {2003-12-01},
journal = {Nat. Immunol.},
volume = {4},
number = {12},
pages = {1159--1160},
keywords = {Animals, Bacterial Physiological Phenomena, Cell Surface, Flagella, Flagellin, Humans, M3i, Membrane Glycoproteins, Receptors, reichhart, Toll-Like Receptor 5, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
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 Journal Article
In: Science, vol. 302, no. 5653, pp. 2126–2130, 2003, ISSN: 1095-9203.
Abstract | Links | BibTeX | Tags: Animals, Carrier Proteins, Cell Surface, DNA Transposable Elements, ferrandon, Gene Expression, Genes, Gram-Negative Bacteria, Gram-Positive Bacteria, Hemolymph, hoffmann, Hypocreales, Insect, Insect Proteins, M3i, Mutation, Phenotype, Receptors, Serine Endopeptidases, Toll-Like Receptors
@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 = {Animals, Carrier Proteins, Cell Surface, DNA Transposable Elements, ferrandon, Gene Expression, Genes, Gram-Negative Bacteria, Gram-Positive Bacteria, Hemolymph, hoffmann, Hypocreales, Insect, Insect Proteins, M3i, Mutation, Phenotype, Receptors, Serine Endopeptidases, Toll-Like Receptors},
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.
Goto Akira, Blandin Stéphanie A, Royet Julien, Reichhart Jean-Marc, Levashina Elena A
Silencing of Toll pathway components by direct injection of double-stranded RNA into Drosophila adult flies Journal Article
In: Nucleic Acids Res., vol. 31, no. 22, pp. 6619–6623, 2003, ISSN: 1362-4962.
Abstract | BibTeX | Tags: Animals, blandin, Cell Surface, Double-Stranded, Epistasis, Female, Genetic, Green Fluorescent Proteins, Homeodomain Proteins, Luminescent Proteins, M3i, Phenotype, Receptors, reichhart, RNA, RNA Interference, Serpins, Signal Transduction, Time Factors, Toll-Like Receptors, Transcription Factors
@article{goto_silencing_2003,
title = {Silencing of Toll pathway components by direct injection of double-stranded RNA into Drosophila adult flies},
author = {Akira Goto and Stéphanie A Blandin and Julien Royet and Jean-Marc Reichhart and Elena A Levashina},
issn = {1362-4962},
year = {2003},
date = {2003-11-01},
journal = {Nucleic Acids Res.},
volume = {31},
number = {22},
pages = {6619--6623},
abstract = {Double-stranded RNA (dsRNA) gene interference is an efficient method to silence gene expression in a sequence-specific manner. Here we show that the direct injection of dsRNA can be used in adult Drosophila flies to disrupt function of endogenous genes in vivo. As a proof of principle, we have used this method to silence components of a major signaling cascade, the Toll pathway, which controls fruit fly resistance to fungal and Gram-positive bacterial infections. We demonstrate that the knockout is efficient only if dsRNA is injected in 4- or more day-old flies and that it lasts for at least 1 week. Furthermore, we report dsRNA-based epistatic gene analysis via injection of a mixture of two dsRNAs and propose that injection of dsRNA represents a powerful method for rapid functional analysis of genes in Drosophila melanogaster adults, particularly of those whose mutations are lethal during development.},
keywords = {Animals, blandin, Cell Surface, Double-Stranded, Epistasis, Female, Genetic, Green Fluorescent Proteins, Homeodomain Proteins, Luminescent Proteins, M3i, Phenotype, Receptors, reichhart, RNA, RNA Interference, Serpins, Signal Transduction, Time Factors, Toll-Like Receptors, Transcription Factors},
pubstate = {published},
tppubtype = {article}
}
Double-stranded RNA (dsRNA) gene interference is an efficient method to silence gene expression in a sequence-specific manner. Here we show that the direct injection of dsRNA can be used in adult Drosophila flies to disrupt function of endogenous genes in vivo. As a proof of principle, we have used this method to silence components of a major signaling cascade, the Toll pathway, which controls fruit fly resistance to fungal and Gram-positive bacterial infections. We demonstrate that the knockout is efficient only if dsRNA is injected in 4- or more day-old flies and that it lasts for at least 1 week. Furthermore, we report dsRNA-based epistatic gene analysis via injection of a mixture of two dsRNAs and propose that injection of dsRNA represents a powerful method for rapid functional analysis of genes in Drosophila melanogaster adults, particularly of those whose mutations are lethal during development.
Hoffmann Jules A
The immune response of Drosophila Journal Article
In: Nature, vol. 426, no. 6962, pp. 33–38, 2003, ISSN: 1476-4687.
Abstract | Links | BibTeX | Tags: Animals, Cell Surface, hoffmann, Immunity, Innate, M3i, Membrane Glycoproteins, Receptors, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors
@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 = {Animals, Cell Surface, hoffmann, Immunity, Innate, M3i, Membrane Glycoproteins, Receptors, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors},
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.
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 Journal Article
In: Nature Immunology, vol. 4, no. 8, pp. 794–800, 2003, ISSN: 1529-2908.
Abstract | Links | BibTeX | Tags: Animals, Cell Surface, hoffmann, imler, Insect Proteins, M3i, Protein Binding, Protein Structure, Receptors, Signal Transduction, Tertiary, Toll-Like Receptors
@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 = {Animals, Cell Surface, hoffmann, imler, Insect Proteins, M3i, Protein Binding, Protein Structure, Receptors, Signal Transduction, Tertiary, Toll-Like Receptors},
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.
Bilak Hana, Tauszig-Delamasure S, Imler Jean-Luc
Toll and Toll-like receptors in Drosophila Journal Article
In: Biochemical Society Transactions, vol. 31, no. Pt 3, pp. 648–651, 2003, ISSN: 0300-5127.
Abstract | Links | BibTeX | Tags: Animals, Biological Evolution, Cell Surface, Fungi, Genome, Gram-Negative Bacteria, Gram-Positive Bacteria, imler, M3i, Membrane Glycoproteins, Receptors, Toll-Like Receptor 5, Toll-Like Receptors
@article{bilak_toll_2003,
title = {Toll and Toll-like receptors in Drosophila},
author = {Hana Bilak and S Tauszig-Delamasure and Jean-Luc Imler},
doi = {10.1042/},
issn = {0300-5127},
year = {2003},
date = {2003-06-01},
journal = {Biochemical Society Transactions},
volume = {31},
number = {Pt 3},
pages = {648--651},
abstract = {The Drosophila Toll receptor controls the immune response to Gram-positive bacteria and fungi by activating a signalling pathway partially conserved throughout evolution. The Drosophila genome encodes eight additional Toll-related receptors, most of which appear to carry out developmental rather than immune functions. One exception may be Toll-9, which shares structural and functional similarities with mammalian TLRs.},
keywords = {Animals, Biological Evolution, Cell Surface, Fungi, Genome, Gram-Negative Bacteria, Gram-Positive Bacteria, imler, M3i, Membrane Glycoproteins, Receptors, Toll-Like Receptor 5, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
The Drosophila Toll receptor controls the immune response to Gram-positive bacteria and fungi by activating a signalling pathway partially conserved throughout evolution. The Drosophila genome encodes eight additional Toll-related receptors, most of which appear to carry out developmental rather than immune functions. One exception may be Toll-9, which shares structural and functional similarities with mammalian TLRs.
Imler Jean-Luc, Hoffmann Jules A
Toll signaling: the TIReless quest for specificity Journal Article
In: Nature Immunology, vol. 4, no. 2, pp. 105–106, 2003, ISSN: 1529-2908.
Links | BibTeX | Tags: Animals, Cell Surface, Dendritic Cells, hoffmann, Humans, imler, Immunological, Interferon-beta, M3i, Membrane Glycoproteins, Mice, Models, Protein Structure, Receptors, Signal Transduction, Tertiary, Toll-Like Receptors
@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 = {Animals, Cell Surface, Dendritic Cells, hoffmann, Humans, imler, Immunological, Interferon-beta, M3i, Membrane Glycoproteins, Mice, Models, Protein Structure, Receptors, Signal Transduction, Tertiary, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Kambris Zakaria, Bilak Hana, D'Alessandro Rosalba, Belvin Marcia, Imler Jean-Luc, Capovilla Maria
DmMyD88 controls dorsoventral patterning of the Drosophila embryo Journal Article
In: EMBO reports, vol. 4, no. 1, pp. 64–69, 2003, ISSN: 1469-221X.
Abstract | Links | BibTeX | Tags: Adaptor Proteins, Alleles, Animals, Antigens, Base Sequence, Cell Surface, Complementary, Developmental, Differentiation, DNA, DNA Transposable Elements, Egg Proteins, Embryo, Exons, Female, Gene Expression Regulation, Genetically Modified, Genotype, imler, Immunity, Immunologic, Innate, Insertional, M3i, Male, messenger, Morphogenesis, Mutagenesis, Myeloid Differentiation Factor 88, Nonmammalian, Oocytes, Protein Biosynthesis, Protein Structure, Receptors, Reverse Transcriptase Polymerase Chain Reaction, RNA, Signal Transducing, Tertiary, Toll-Like Receptors, Zygote
@article{kambris_dmmyd88_2003,
title = {DmMyD88 controls dorsoventral patterning of the Drosophila embryo},
author = {Zakaria Kambris and Hana Bilak and Rosalba D'Alessandro and Marcia Belvin and Jean-Luc Imler and Maria Capovilla},
doi = {10.1038/sj.embor.embor714},
issn = {1469-221X},
year = {2003},
date = {2003-01-01},
journal = {EMBO reports},
volume = {4},
number = {1},
pages = {64--69},
abstract = {MyD88 is an adapter protein in the signal transduction pathway mediated by interleukin-1 (IL-1) and Toll-like receptors. A Drosophila homologue of MyD88 (DmMyD88) was recently shown to be required for the Toll-mediated immune response. In Drosophila, the Toll pathway was originally characterized for its role in the dorsoventral patterning of the embryo. We found that, like Toll, DmMyD88 messenger RNA is maternally supplied to the embryo. Here we report the identification of a new mutant allele of DmMyD88, which generates a protein lacking the carboxy-terminal extension, normally located downstream of the Toll/IL-1 receptor domain. Homozygous mutant female flies lay dorsalized embryos that are rescued by expression of a transgenic DmMyD88 complementary DNA. The DmMyD88 mutation blocks the ventralizing activity of a gain-of-function Toll mutation. These results show that DmMyD88 encodes an essential component of the Toll pathway in dorsoventral pattern formation.},
keywords = {Adaptor Proteins, Alleles, Animals, Antigens, Base Sequence, Cell Surface, Complementary, Developmental, Differentiation, DNA, DNA Transposable Elements, Egg Proteins, Embryo, Exons, Female, Gene Expression Regulation, Genetically Modified, Genotype, imler, Immunity, Immunologic, Innate, Insertional, M3i, Male, messenger, Morphogenesis, Mutagenesis, Myeloid Differentiation Factor 88, Nonmammalian, Oocytes, Protein Biosynthesis, Protein Structure, Receptors, Reverse Transcriptase Polymerase Chain Reaction, RNA, Signal Transducing, Tertiary, Toll-Like Receptors, Zygote},
pubstate = {published},
tppubtype = {article}
}
MyD88 is an adapter protein in the signal transduction pathway mediated by interleukin-1 (IL-1) and Toll-like receptors. A Drosophila homologue of MyD88 (DmMyD88) was recently shown to be required for the Toll-mediated immune response. In Drosophila, the Toll pathway was originally characterized for its role in the dorsoventral patterning of the embryo. We found that, like Toll, DmMyD88 messenger RNA is maternally supplied to the embryo. Here we report the identification of a new mutant allele of DmMyD88, which generates a protein lacking the carboxy-terminal extension, normally located downstream of the Toll/IL-1 receptor domain. Homozygous mutant female flies lay dorsalized embryos that are rescued by expression of a transgenic DmMyD88 complementary DNA. The DmMyD88 mutation blocks the ventralizing activity of a gain-of-function Toll mutation. These results show that DmMyD88 encodes an essential component of the Toll pathway in dorsoventral pattern formation.
2002
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 Journal Article
In: EMBO J., vol. 21, no. 23, pp. 6330–6337, 2002, ISSN: 0261-4189.
Abstract | BibTeX | Tags: Animals, Cell Surface, Hemolymph, hoffmann, infection, M3i, Melanins, Receptors, reichhart, Serpins, Toll-Like Receptors
@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 = {Animals, Cell Surface, Hemolymph, hoffmann, infection, M3i, Melanins, Receptors, reichhart, Serpins, Toll-Like Receptors},
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.
Kambris Zakaria, Hoffmann Jules A, Imler Jean-Luc, Capovilla Maria
Tissue and stage-specific expression of the Tolls in Drosophila embryos Journal Article
In: Gene expression patterns: GEP, vol. 2, no. 3-4, pp. 311–317, 2002, ISSN: 1567-133X.
Abstract | BibTeX | Tags: Animals, Blotting, Cell Surface, Gene Expression Profiling, hoffmann, imler, Larva, M3i, Multigene Family, Northern, Receptors, Toll-Like Receptors
@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 = {Animals, Blotting, Cell Surface, Gene Expression Profiling, hoffmann, imler, Larva, M3i, Multigene Family, Northern, Receptors, Toll-Like Receptors},
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.
Ligoxygakis Petros, Pelte Nadège, Hoffmann Jules A, Reichhart Jean-Marc
Activation of Drosophila Toll during fungal infection by a blood serine protease Journal Article
In: Science, vol. 297, no. 5578, pp. 114–116, 2002, ISSN: 1095-9203.
Abstract | Links | BibTeX | Tags: Animals, Cell Surface, Chromosome Mapping, Escherichia coli, Female, Gene Expression Regulation, Genes, Gram-Positive Cocci, Hemolymph, hoffmann, Hypocreales, Insect, Insect Proteins, M3i, Male, Mutation, Protein Sorting Signals, Protein Structure, Receptors, reichhart, Serine Endopeptidases, Tertiary, Toll-Like Receptors
@article{ligoxygakis_activation_2002,
title = {Activation of Drosophila Toll during fungal infection by a blood serine protease},
author = {Petros Ligoxygakis and Nadège Pelte and Jules A Hoffmann and Jean-Marc Reichhart},
doi = {10.1126/science.1072391},
issn = {1095-9203},
year = {2002},
date = {2002-07-01},
journal = {Science},
volume = {297},
number = {5578},
pages = {114--116},
abstract = {Drosophila host defense to fungal and Gram-positive bacterial infection is mediated by the Spaetzle/Toll/cactus gene cassette. It has been proposed that Toll does not function as a pattern recognition receptor per se but is activated through a cleaved form of the cytokine Spaetzle. The upstream events linking infection to the cleavage of Spaetzle have long remained elusive. Here we report the identification of a central component of the fungal activation of Toll. We show that ethylmethane sulfonate-induced mutations in the persephone gene, which encodes a previously unknown serine protease, block induction of the Toll pathway by fungi and resistance to this type of infection.},
keywords = {Animals, Cell Surface, Chromosome Mapping, Escherichia coli, Female, Gene Expression Regulation, Genes, Gram-Positive Cocci, Hemolymph, hoffmann, Hypocreales, Insect, Insect Proteins, M3i, Male, Mutation, Protein Sorting Signals, Protein Structure, Receptors, reichhart, Serine Endopeptidases, Tertiary, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
Drosophila host defense to fungal and Gram-positive bacterial infection is mediated by the Spaetzle/Toll/cactus gene cassette. It has been proposed that Toll does not function as a pattern recognition receptor per se but is activated through a cleaved form of the cytokine Spaetzle. The upstream events linking infection to the cleavage of Spaetzle have long remained elusive. Here we report the identification of a central component of the fungal activation of Toll. We show that ethylmethane sulfonate-induced mutations in the persephone gene, which encodes a previously unknown serine protease, block induction of the Toll pathway by fungi and resistance to this type of infection.
Hoffmann Jules A, Reichhart Jean-Marc
Drosophila innate immunity: an evolutionary perspective Journal Article
In: Nat. Immunol., vol. 3, no. 2, pp. 121–126, 2002, ISSN: 1529-2908.
Abstract | Links | BibTeX | Tags: Animals, Biological Evolution, Cell Surface, hoffmann, Immunity, Immunological, Innate, M3i, Membrane Glycoproteins, Models, Receptors, reichhart, Signal Transduction, Toll-Like Receptors
@article{hoffmann_drosophila_2002,
title = {Drosophila innate immunity: an evolutionary perspective},
author = {Jules A Hoffmann and Jean-Marc Reichhart},
doi = {10.1038/ni0202-121},
issn = {1529-2908},
year = {2002},
date = {2002-02-01},
journal = {Nat. Immunol.},
volume = {3},
number = {2},
pages = {121--126},
abstract = {In response to microbial infections, Drosophila mounts a multifaceted immune response involving humoral reactions that culminate in the destruction of invading organisms by lytic peptides. These defense mechanisms are activated via two distinct signaling pathways. One of these, the Toll pathway, controls resistance to fungal and Gram-positive bacterial infections, whereas the Imd pathway is responsible for defense against Gram-negative bacterial infections. Current evidence indicates that recognition of infectious nonself agents results from interactions between microbial wall components and extracellular pattern recognition proteins. We discuss here evolutionary perspectives on our present understanding of the antimicrobial defenses of Drosophila.},
keywords = {Animals, Biological Evolution, Cell Surface, hoffmann, Immunity, Immunological, Innate, M3i, Membrane Glycoproteins, Models, Receptors, reichhart, Signal Transduction, Toll-Like Receptors},
pubstate = {published},
tppubtype = {article}
}
In response to microbial infections, Drosophila mounts a multifaceted immune response involving humoral reactions that culminate in the destruction of invading organisms by lytic peptides. These defense mechanisms are activated via two distinct signaling pathways. One of these, the Toll pathway, controls resistance to fungal and Gram-positive bacterial infections, whereas the Imd pathway is responsible for defense against Gram-negative bacterial infections. Current evidence indicates that recognition of infectious nonself agents results from interactions between microbial wall components and extracellular pattern recognition proteins. We discuss here evolutionary perspectives on our present understanding of the antimicrobial defenses of Drosophila.
Tauszig-Delamasure Servane, Bilak Hana, Capovilla Maria, Hoffmann Jules A, Imler Jean-Luc
Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections Journal Article
In: Nature Immunology, vol. 3, no. 1, pp. 91–97, 2002, ISSN: 1529-2908.
Abstract | Links | BibTeX | Tags: Adaptor Proteins, Amino Acid, Animals, Antigens, Antimicrobial Cationic Peptides, Cell Surface, Chromosome Mapping, Differentiation, Disease Susceptibility, Enterococcus faecalis, Epistasis, Escherichia coli, Female, Gene Expression Regulation, Genes, Genetic, Genetically Modified, Gram-Negative Bacteria, hoffmann, Hypocreales, imler, Immunologic, Insect, Insect Proteins, M3i, Membrane Glycoproteins, Micrococcus luteus, Myeloid Differentiation Factor 88, Protein Structure, Protein-Serine-Threonine Kinases, Receptors, Recombinant Fusion Proteins, Sequence Alignment, Sequence Homology, Signal Transducing, Tertiary, Toll-Like Receptors, Transfection
@article{tauszig-delamasure_drosophila_2002,
title = {Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections},
author = {Servane Tauszig-Delamasure and Hana Bilak and Maria Capovilla and Jules A Hoffmann and Jean-Luc Imler},
doi = {10.1038/ni747},
issn = {1529-2908},
year = {2002},
date = {2002-01-01},
journal = {Nature Immunology},
volume = {3},
number = {1},
pages = {91--97},
abstract = {We report here the identification and functional characterization of DmMyD88, a gene encoding the Drosophila homolog of mammalian MyD88. DmMyD88 combines a Toll-IL-1R homology (TIR) domain and a death domain. Overexpression of DmMyD88 was sufficient to induce expression of the antifungal peptide Drosomycin, and induction of Drosomycin was markedly reduced in DmMyD88-mutant flies. DmMyD88 interacted with Toll through its TIR domain and required the death domain proteins Tube and Pelle to activate expression of Drs, which encodes Drosomycin. DmMyD88-mutant flies were highly susceptible to infection by fungi and Gram-positive bacteria, but resisted Gram-negative bacterial infection much as did wild-type flies. Phenotypic comparison of DmMyD88-mutant flies and MyD88-deficient mice showed essential differences in the control of Gram-negative infection in insects and mammals.},
keywords = {Adaptor Proteins, Amino Acid, Animals, Antigens, Antimicrobial Cationic Peptides, Cell Surface, Chromosome Mapping, Differentiation, Disease Susceptibility, Enterococcus faecalis, Epistasis, Escherichia coli, Female, Gene Expression Regulation, Genes, Genetic, Genetically Modified, Gram-Negative Bacteria, hoffmann, Hypocreales, imler, Immunologic, Insect, Insect Proteins, M3i, Membrane Glycoproteins, Micrococcus luteus, Myeloid Differentiation Factor 88, Protein Structure, Protein-Serine-Threonine Kinases, Receptors, Recombinant Fusion Proteins, Sequence Alignment, Sequence Homology, Signal Transducing, Tertiary, Toll-Like Receptors, Transfection},
pubstate = {published},
tppubtype = {article}
}
We report here the identification and functional characterization of DmMyD88, a gene encoding the Drosophila homolog of mammalian MyD88. DmMyD88 combines a Toll-IL-1R homology (TIR) domain and a death domain. Overexpression of DmMyD88 was sufficient to induce expression of the antifungal peptide Drosomycin, and induction of Drosomycin was markedly reduced in DmMyD88-mutant flies. DmMyD88 interacted with Toll through its TIR domain and required the death domain proteins Tube and Pelle to activate expression of Drs, which encodes Drosomycin. DmMyD88-mutant flies were highly susceptible to infection by fungi and Gram-positive bacteria, but resisted Gram-negative bacterial infection much as did wild-type flies. Phenotypic comparison of DmMyD88-mutant flies and MyD88-deficient mice showed essential differences in the control of Gram-negative infection in insects and mammals.
Imler Jean-Luc, Hoffmann Jules A
Toll receptors in Drosophila: a family of molecules regulating development and immunity Journal Article
In: Current Topics in Microbiology and Immunology, vol. 270, pp. 63–79, 2002, ISSN: 0070-217X.
Abstract | BibTeX | Tags: Animals, Cell Surface, Genetic, Gram-Negative Bacteria, hoffmann, imler, M3i, Receptors, Signal Transduction, Toll-Like Receptors, Transcription
@article{imler_toll_2002,
title = {Toll receptors in Drosophila: a family of molecules regulating development and immunity},
author = {Jean-Luc Imler and Jules A Hoffmann},
issn = {0070-217X},
year = {2002},
date = {2002-01-01},
journal = {Current Topics in Microbiology and Immunology},
volume = {270},
pages = {63--79},
abstract = {In recent years, Toll-like receptors (TLRs) have emerged as key receptors which detect microbes and initiate an inflammatory response. The Toll receptor was originally identified and characterized 14 years ago for its role in the embryonic development of the fruit-fly Drosophila melanogaster. Subsequently, it was also shown to be an essential component of the signaling pathway mediating the anti-fungal host defense in this model organism. New factors involved in the activation of the Toll receptor or in intracytoplasmic signaling during the immune response in Drosophila have recently been identified. The existence of significant functional differences between mammalian TLRs and Drosophila Toll receptors is also becoming apparent.},
keywords = {Animals, Cell Surface, Genetic, Gram-Negative Bacteria, hoffmann, imler, M3i, Receptors, Signal Transduction, Toll-Like Receptors, Transcription},
pubstate = {published},
tppubtype = {article}
}
In recent years, Toll-like receptors (TLRs) have emerged as key receptors which detect microbes and initiate an inflammatory response. The Toll receptor was originally identified and characterized 14 years ago for its role in the embryonic development of the fruit-fly Drosophila melanogaster. Subsequently, it was also shown to be an essential component of the signaling pathway mediating the anti-fungal host defense in this model organism. New factors involved in the activation of the Toll receptor or in intracytoplasmic signaling during the immune response in Drosophila have recently been identified. The existence of significant functional differences between mammalian TLRs and Drosophila Toll receptors is also becoming apparent.
2001
Michel T, Reichhart Jean-Marc, Hoffmann Jules A, Royet Julien
Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein Journal Article
In: Nature, vol. 414, no. 6865, pp. 756–759, 2001, ISSN: 0028-0836.
Abstract | Links | BibTeX | Tags: Amino Acid, Animals, Anti-Bacterial Agents, Anti-Infective Agents, Bacillus thuringiensis, Carrier Proteins, Cell Surface,