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Jules A. HOFFMANN
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HOFFMANN A. Jules
UPR 9022 du CNRS
Institut de Biologie Moléculaire et Cellulaire
15, rue René Descartes
67084 Strasbourg Cedex, FRANCE
E-mail : J.Hoffmann@unistra.fr
Tel : 03 88 41 70 77
+033 672 66 88 54
Fax : 03 88 60 69 22
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Directeur de Recherche de Classe Exceptionnelle
(Emérite depuis 2009)
Membre
de l'Académie des Sciences, Paris
Professeur Conventionné à l'Université de Strasbourg
Membre de l'Académie des Sciences et des Arts des Etats-Unis d'Amérique
J. Hoffmann a fait ses études
universitaires à Strasbourg où il a soutenu sa thèse en biologie expérimentale.
Il y a fait toute sa carrière, d’abord à l’Institut de Zoologie, puis à
l’Institut de Biologie Moléculaire et Cellulaire, dont il fut le Directeur de
1992 à 2005. Membre de l’Académie des Sciences, dont il assura la
Vice-Présidence puis la Présidence de 2005 à 2008, J. Hoffmann est également
Membre des Académies des Sciences des Etats-Unis, d’Allemagne et de Russie. Les
recherches de J. Hoffmann et de ses nombreux collaborateurs ont établi la
drosophile comme modèle de recherche de l’immunité innée. Ils ont permis de
décrypter la nature des récepteurs reconnaissant les agents pathogènes,
d’établir les voies de signalisation qui sont déclenchées au cours des
infections, et qui contrôlent l’expression des gènes codant pour les protéines
de la réponse immune, notamment pour des peptides antimicrobiens. L’ensemble de
ces travaux et particulièrement la découverte du rôle des récepteurs Toll, a
conduit à réévaluer le rôle de l’immunité innée chez les Mammifères et a contribué
au renouvellement de ce domaine négligé en immunologie. J. Hoffmann a reçu le
Grand Prix de la Fondation de la Recherche Médicale, le Prix Robert Koch
d’Immunologie, le William Cooley Award, le Prix Balzan, le Prix Lewis
Rosenstiel et tout récemment le Prix Keio for Medical Sciences. |
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| Curriculum Vitae (PDF) |
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Publications de Jules A. HOFFMANN
| Titre, Autheur(s) | Journal, Références | | Broad RNA interference-mediated antiviral immunity and virus-specific inducible responses in Drosophila.
Kemp C, Mueller S, Goto A, Barbier V, Paro S, Bonnay F, Dostert C, Troxler L, Hetru C, Meignin C, Pfeffer S, Hoffmann JA, Imler JL.
Abstract : The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. The response of Drosophila to virus infections remains poorly characterized and appears to involve two facets. On the one hand, RNA interference involves the recognition and processing of dsRNA into small interfering RNAs by the host RNase Dicer-2 (Dcr-2), whereas, on the other hand, an inducible response controlled by the evolutionarily conserved JAK-STAT pathway contributes to the antiviral host defense. To clarify the contribution of the small interfering RNA and JAK-STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type and mutant for Dcr-2 or the JAK kinase Hopscotch to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by Drosophila C virus and cricket paralysis virus, two members of the Dicistroviridae family, which contrasts with the susceptibility of Dcr-2 mutant flies to many viruses, including the DNA virus invertebrate iridescent virus 6. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by Drosophila C virus or by two unrelated RNA viruses, Flock House virus and Sindbis virus. Overall, our data reveal that RNA interference is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK-STAT pathway appears to be virus specific.
| J Immunol.
2013 Jan 15;190(2):650-8 | Abstract
Article complet | Drosophila EYA regulates the immune response against DNA through an evolutionarily conserved threonine phosphatase motif.
Liu X, Sano T, Guan Y, Nagata S, Hoffmann JA, Fukuyama H
Abstract : Innate immune responses against DNA are essential to counter both pathogen infections and tissue damages. Mammalian EYAs were recently shown to play a role in regulating the innate immune responses against DNA. Here, we demonstrate that the unique Drosophila eya gene is also involved in the response specific to DNA. Haploinsufficiency of eya in mutants deficient for lysosomal DNase activity (DNaseII) reduces antimicrobial peptide gene expression, a hallmark for immune responses in flies. Like the mammalian orthologues, Drosophila EYA features a N-terminal threonine and C-terminal tyrosine phosphatase domain. Through the generation of a series of mutant EYA fly strains, we show that the threonine phosphatase domain, but not the tyrosine phosphatase domain, is responsible for the innate immune response against DNA. A similar role for the threonine phosphatase domain in mammalian EYA4 had been surmised on the basis of in vitro studies. Furthermore EYA associates with IKKβ and full-length RELISH, and the induction of the IMD pathway-dependent antimicrobial peptide gene is independent of SO. Our data provide the first in vivo demonstration for the immune function of EYA and point to their conserved immune function in response to endogenous DNA, throughout evolution.
| PLoS One.
2012;7(8):e42725 | Abstract
Article complet | RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila
Mueller S, Gausson V, Vodovar N, Deddouche S, Troxler L, Perot J, Pfeffer S, Hoffmann JA, Saleh MC, Imler JL
Abstract : Activation of innate antiviral responses in multicellular organisms relies on the recognition of structural differences between viral and cellular RNAs. Double-stranded (ds)RNA, produced during viral replication, is a well-known activator of antiviral defenses and triggers interferon production in vertebrates and RNAi in invertebrates and plants. Previous work in mammalian cells indicates that negative-strand RNA viruses do not appear to generate dsRNA, and that activation of innate immunity is triggered by the recognition of the uncapped 5' ends of viral RNA. This finding raises the question whether antiviral RNAi, which is triggered by the presence of dsRNA in insects, represents an effective host-defense mechanism against negative-strand RNA viruses. Here, we show that the negative-strand RNA virus vesicular stomatitis virus (VSV) does not produce easily detectable amounts of dsRNA in Drosophila cells. Nevertheless, RNAi represents a potent response to VSV infection, as illustrated by the high susceptibility of RNAi-defective mutant flies to this virus. VSV-derived small RNAs produced in infected cells or flies uniformly cover the viral genome, and equally map the genome and antigenome RNAs, indicating that they derive from dsRNA. Our findings reveal that RNAi is not restricted to the defense against positive-strand or dsRNA viruses but can also be highly efficient against a negative-strand RNA virus. This result is of particular interest in view of the frequent transmission of medically relevant negative-strand RNA viruses to humans by insect vectors.
| Proc Natl Acad Sci USA
2010 Nov 9;107(45):19390-5 | Abstract
Article complet | The N-terminal domain of drosophila gram-negative binding protein 3 (GNBP3) defines a novel family of fungal pattern recognition receptors.
Mishima Y, Quintin J, Aimanianda V, Kellenberger C, Coste F, Clavaud C, Hetru C, Hoffmann JA, Latgé JP, Ferrandon D, Roussel A.
Abstract : GNBP3, a pattern recognition receptor (PRR) that circulates in the hemolymph of Drosophila, is responsible for sensing fungal infection and triggering Toll pathway activation. Here, we report that GNBP3 N-terminal domain binds to fungi upon identifying long chains of beta-1,3-glucans in the fungal cell wall as a major ligand. Interestingly, this domain fails to interact strongly with short oligosaccharides. The crystal structure of GNBP3-Nter reveals an immunoglobulin-like fold in which the glucan binding site is masked by a loop that is highly conserved among glucan binding proteins identified in several insect orders. Structure-based mutagenesis experiments reveal an essential role for this occluding loop in discriminating between short and long polysaccharides. The displacement of the occluding loop is necessary for binding and could explain the specificity of the interaction with long chain structured polysaccharides. This represents a novel mechanism for beta-glucan recognition.
| Journal of Biological Chemistry.
2009 Oct 16;284(42):28687-97. Epub 2009 Aug 19. | Abstract
Article complet | Two mosquito LRR proteins function as complement control factors in the TEP1-mediated killing of Plasmodium.
Fraiture M, Baxter RH, Steinert S, Chelliah Y, Frolet C, Quispe-Tintaya W, Hoffmann JA, Blandin SA, Levashina EA.
Abstract : Plasmodium development within Anopheles mosquitoes is a vulnerable step in the parasite transmission cycle, and targeting this step represents a promising strategy for malaria control. The thioester-containing complement-like protein TEP1 and two leucine-rich repeat (LRR) proteins, LRIM1 and APL1, have been identified as major mosquito factors that regulate parasite loads. Here, we show that LRIM1 and APL1 are required for binding of TEP1 to parasites. RNAi silencing of the LRR-encoding genes results in deposition of TEP1 on Anopheles tissues, thereby depleting TEP1 from circulation in the hemolymph and impeding its binding to Plasmodium. LRIM1 and APL1 not only stabilize circulating TEP1, they also stabilize each other prior to their interaction with TEP1. Our results indicate that three major antiparasitic factors in mosquitoes jointly function as a complement-like system in parasite killing, and they reveal a role for LRR proteins as complement control factors.
| Cell Host Microbe.
2009 Mar 19;5(3):273-84 | Abstract
Article complet | The DEXD/H-box helicase Dicer-2 mediates induction of an antiviral activity in drosophila
Deddouche S., Matt N., Budd A., Mueller S., Kemp C., Galiana-Arnoux D., Dostert C., Antoniewski C., Hoffmann J.A. & Imler J.L.
Abstract : Drosophila, like other invertebrates and plants, relies mainly on RNA interference for its defense against viruses. In flies, viral infection also triggers the expression of many genes. One of the genes induced, Vago, encodes a 18-kilodalton cysteine-rich polypeptide. Here we provide genetic evidence that the Vago gene product controlled viral load in the fat body after infection with drosophila C virus. Induction of Vago was dependent on the helicase Dicer-2. Dicer-2 belongs to the same DExD/H-box helicase family as do the RIG-I-like receptors, which sense viral infection and mediate interferon induction in mammals. We propose that this family represents an evolutionary conserved set of sensors that detect viral nucleic acids and direct antiviral responses.
| Nature Immunology
2008: Vol. 9, 1425-1432 | Abstract
Article complet | Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in Drosophila and mice
Goto A, Matsushita K, Gesellchen V, El Chamy L, Kuttenkeuler D, Takeuchi O, Hoffmann JA, Akira S, Boutros M, Reichhart JM
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.
| Nature Immunology
2008 : Vol 9, 97-104 | Abstract
Article complet | A Model of Bacterial Intestinal Infections in Drosophila melanogaster
Nehme NT, Liégeois S, Kele B, Giammarinaro P, Pradel E, Hoffmann J, Ewbank JJ, and Ferrandon D
Abstract : Serratia marcescens is an entomopathogenic bacterium that opportunistically infects a wide range of hosts, including humans. In a model of septic injury, if directly introduced into the body cavity of Drosophila, this pathogen is insensitive to the host's systemic immune response and kills flies in a day. We find that S. marcescens resistance to the Drosophila immune deficiency (imd)-mediated humoral response requires the bacterial lipopolysaccharide O-antigen. If ingested by Drosophila, bacteria cross the gut and penetrate the body cavity. During this passage, the bacteria can be observed within the cells of the intestinal epithelium. In such an oral infection model, the flies succumb to infection only after 6 days. We demonstrate that two complementary host defense mechanisms act together against such food-borne infection: an antimicrobial response in the intestine that is regulated by the imd pathway and phagocytosis by hemocytes of bacteria that have escaped into the hemolymph. Interestingly, bacteria present in the hemolymph elicit a systemic immune response only when phagocytosis is blocked. Our observations support a model wherein peptidoglycan fragments released during bacterial growth activate the imd pathway and do not back a proposed role for phagocytosis in the immune activation of the fat body. Thanks to the genetic tools available in both host and pathogen, the molecular dissection of the interactions between S. marcescens and Drosophila will provide a useful paradigm for deciphering intestinal pathogenesis.
| PloS Pathog
2007: | Abstract
Article complet | The Drosophila systemic immune response : sensing and signalling during bactrial and fungal infections
Ferrandon D, Imler JL, Hetru C, Hoffmann JA
Abstract : A hallmark of the potent, multifaceted antimicrobial defence of Drosophila melanogaster is the challenge-induced synthesis of several families of antimicrobial peptides by cells in the fat body. The basic mechanisms of recognition of various types of microbial infections by the adult fly are now understood, often in great detail. We have further gained valuable insight into the infection-induced gene reprogramming by nuclear factor-kappaB (NF-kappaB) family members under the dependence of complex intracellular signalling cascades. The striking parallels between the adult fly response and mammalian innate immune defences described below point to a common ancestry and validate the relevance of the fly defence as a paradigm for innate immunity.
| Nature Reviews of Immunology
2007 : Vol 7, 862-874 | Abstract
Article complet | Genetic analysis of resistance to viral infection
Beutler B, Eidenschenk C, Crozat K, Imler JL, Takeuchi O, Hoffmann JA, Akira S
Abstract : As machines that reprogramme eukaryotic cells to suit their own purposes, viruses present a difficult problem for multicellular hosts, and indeed, have become one of the central pre-occupations of the immune system. Unable to permanently outpace individual viruses in an evolutionary footrace, higher eukaryotes have evolved broadly active mechanisms with which to sense viruses and suppress their proliferation. These mechanisms have recently been elucidated by a combination of forward and reverse genetic methods. Some of these mechanisms are clearly ancient, whereas others are relatively new. All are remarkably adept at discriminating self from non-self, and allow the host to cope with what might seem an impossible predicament.
| Nature Reviews of Immunology
2007 : Vol 7, 753-766 | Abstract
Article complet | Antifungal defense in Drosophila
Hoffmann JA
Abstract :
| Nature Immunology
2007 : Vol 8, 543-545 | Abstract
Article complet | The host defense of Drosophila melanogaster
Lemaitre B, Hoffmann JA
Abstract : To combat infection, the fruit fly Drosophila melanogaster relies on multiple innate defense reactions, many of which are shared with higher organisms. These reactions include the use of physical barriers together with local and systemic immune responses. First, epithelia, such as those beneath the cuticle, in the alimentary tract, and in tracheae, act both as a physical barrier and local defense against pathogens by producing antimicrobial peptides and reactive oxygen species. Second, specialized hemocytes participate in phagocytosis and encapsulation of foreign intruders in the hemolymph. Finally, the fat body, a functional equivalent of the mammalian liver, produces humoral response molecules including antimicrobial peptides. Here we review our current knowledge of the molecular mechanisms underlying Drosophila defense reactions together with strategies evolved by pathogens to evade them.
| Annual Review of Immunology
2007 : Vol 25, 697-743 | Abstract
Article complet | Dual Detection of Fungal Infections in Drosophila via Recognition of Glucans and Sensing of Virulence Factors
Gottar M, Gobert V, Matskevich AA, Reichhart JM, Wang C, Butt TM, Belvin M, Hoffmann JA, Ferrandon D
Abstract : The Drosophila immune system discriminates between various types of infections and activates appropriate signal transduction pathways to combat the invading microorganisms. The Toll pathway is required for the host response against fungal and most Gram-positive bacterial infections. The sensing of Gram-positive bacteria is mediated by the pattern recognition receptors PGRP-SA and GNBP1 that cooperate to detect the presence of infections in the host. Here, we report that GNBP3 is a pattern recognition receptor that is required for the detection of fungal cell wall components. Strikingly, we find that there is a second, parallel pathway acting jointly with GNBP3. The Drosophila Persephone protease activates the Toll pathway when proteolytically matured by the secreted fungal virulence factor PR1. Thus, the detection of fungal infections in Drosophila relies both on the recognition of invariant microbial patterns and on monitoring the effects of virulence factors on the host.
| Cell
2006: Vol 127, 1425-37. | Abstract
Article complet | Fz2 and cdc42 mediate melanization and actin polymerization but are dispensable for Plasmodium killing in the mosquito midgut
Shiao SH, Whitten MM, Zachary D, Hoffmann JA, Levashina EA
Abstract : The midgut epithelium of the mosquito malaria vector Anopheles is a hostile environment for Plasmodium, with most parasites succumbing to host defenses. This study addresses morphological and ultrastructural features associated with Plasmodium berghei ookinete invasion in Anopheles gambiae midguts to define the sites and possible mechanisms of parasite killing. We show by transmission electron microscopy and immunofluorescence that the majority of ookinetes are killed in the extracellular space. Dead or dying ookinetes are surrounded by a polymerized actin zone formed within the basal cytoplasm of adjacent host epithelial cells. In refractory strain mosquitoes, we found that formation of this zone is strongly linked to prophenoloxidase activation leading to melanization. Furthermore, we identify two factors controlling both phenomena: the transmembrane receptor frizzled-2 and the guanosine triphosphate-binding protein cell division cycle 42. However, the disruption of actin polymerization and melanization by double-stranded RNA inhibition did not affect ookinete survival. Our results separate the mechanisms of parasite killing from subsequent reactions manifested by actin polymerization and prophenoloxidase activation in the A. gambiae-P. berghei model. These latter processes are reminiscent of wound healing in other organisms, and we propose that they represent a form of wound-healing response directed towards a moribund ookinete, which is perceived as damaged tissue.
| PLoS Pathog.
2006: Vol 2, 1152-1164 | Abstract
Article complet | Boosting NF-κB-Dependent Basal Immunity of Anopheles gambiae Aborts Development of Plasmodium berghei
Frolet C, Thoma M, Blandin S, Hoffmann JA, Levashina EA
Abstract : Anopheles gambiae, the major vector for the protozoan malaria parasite Plasmodium falciparum, mounts powerful antiparasitic responses that cause marked parasite loss during midgut invasion. Here, we showed that these antiparasitic defenses were composed of pre- and postinvasion phases and that the preinvasion phase was predominantly regulated by Rel1 and Rel2 members of the NF-kappaB transcription factors. Concurrent silencing of Rel1 and Rel2 decreased the basal expression of the major antiparasitic genes TEP1 and LRIM1 and abolished resistance of Anopheles to the rodent malaria parasite P. berghei. Conversely, depletion of a negative regulator of Rel1, Cactus, prior to infection, enhanced the basal expression of TEP1 and of other immune factors and completely prevented parasite development. Our findings uncover the crucial role of the preinvasion defense in the elimination of parasites, which is at least in part based on circulating blood molecules.
| Immunity
2006: Vol 25, 677-85. | Abstract
Article complet | Prophenoloxidase activation is not required for survival to microbial infections in Drosophila
Leclerc V, Pelte, N, El Chamy L, Martinelli C, Ligoxygakis P, Hoffmann JA and Reichhart JM
Abstract : he antimicrobial defence of Drosophila relies on cellular and humoral processes, of which the inducible synthesis of antimicrobial peptides has attracted interest in recent years. Another potential line of defence is the activation, by a proteolytic cascade, of phenoloxidase, which leads to the production of quinones and melanin. However, in spite of several publications on this subject, the contribution of phenoloxidase activation to resistance to infections has not been established under appropriate in vivo conditions. Here, we have isolated the first Drosophila mutant for a prophenoloxidase-activating enzyme (PAE1). In contrast to wild-type flies, PAE1 mutants fail to activate phenoloxidase in the haemolymph following microbial challenge. Surprisingly, we find that these mutants are as resistant to infections as wild-type flies, in the total absence of circulating phenoloxidase activity. This raises the question with regard to the precise function of phenoloxidase activation in defence, if any.
| EMBO Rep
2006 : (2):231-5 | Abstract
Article complet | Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila
Galiana-Arnoux D, Dostert C, Schneemann A, Hoffmann JA, Imler JL
Abstract : The fruit fly Drosophila melanogaster is a model system for studying innate immunity, including antiviral host defense. Infection with drosophila C virus triggers a transcriptional response that is dependent in part on the Jak kinase Hopscotch. Here we show that successful infection and killing of drosophila with the insect nodavirus flock house virus was strictly dependent on expression of the viral protein B2, a potent inhibitor of processing of double-stranded RNA mediated by the essential RNA interference factor Dicer. Conversely, flies with a loss-of-function mutation in the gene encoding Dicer-2 (Dcr-2) showed enhanced susceptibility to infection by flock house virus, drosophila C virus and Sindbis virus, members of three different families of RNA viruses. These data demonstrate the importance of RNA interference for controlling virus replication in vivo and establish Dcr-2 as a host susceptibility locus for virus infections.
| Nature Immunology
2006: Vol 7, 590 - 597 | Abstract
Article complet | Prophenoloxidase activation is not required for survival to microbial infections in Drosophila
Leclerc V, Pelte N, ElChamy L, Martinelli C, Ligoxygakis P, Hoffmann JA, Reichhart JM
Abstract : The antimicrobial defence of Drosophila relies on cellular and humoral processes, of which the inducible synthesis of antimicrobial peptides has attracted interest in recent years. Another potential line of defence is the activation, by a proteolytic cascade, of phenoloxidase, which leads to the production of quinones and melanin. However, in spite of several publications on this subject, the contribution of phenoloxidase activation to resistance to infections has not been established under appropriate in vivo conditions. Here, we have isolated the first Drosophila mutant for a prophenoloxidase-activating enzyme (PAE1). In contrast to wild-type flies, PAE1 mutants fail to activate phenoloxidase in the haemolymph following microbial challenge. Surprisingly, we find that these mutants are as resistant to infections as wild-type flies, in the total absence of circulating phenoloxidase activity. This raises the question with regard to the precise function of phenoloxidase activation in defence, if any.
| EMBO Reports
2006: Vol 7, 231-235 | Abstract
Article complet | Downregulation of the Drosophila Immune Response by Peptidoglycan-Recognition Proteins SC1 and SC2
Bischoff V, Vignal C, Duvic B, Boneca IG, Hoffmann JA, Royet J
Abstract : Peptidoglycan-recognition proteins (PGRPs) are evolutionarily conserved molecules that are structurally related to bacterial amidases. Several Drosophila PGRPs have lost this enzymatic activity and serve as microbe sensors through peptidoglycan recognition. Other PGRP family members, such as Drosophila PGRP-SC1 or mammalian PGRP-L, have conserved the amidase function and are able to cleave peptidoglycan in vitro. However, the contribution of these amidase PGRPs to host defense in vivo has remained elusive so far. Using an RNA-interference approach, we addressed the function of two PGRPs with amidase activity in the Drosophila immune response. We observed that PGRP-SC1/2-depleted flies present a specific over-activation of the IMD (immune deficiency) signaling pathway after bacterial challenge. Our data suggest that these proteins act in the larval gut to prevent activation of this pathway following bacterial ingestion. We further show that a strict control of IMD-pathway activation is essential to prevent bacteria-induced developmental defects and larval death.
| PLoS Pathog
2006: Vol 2, 139-147 | Abstract
Article complet | The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of Drosophila
Dostert C, Jouanguy E, Irving P, Troxler L, Galiana-Arnoux D, Hetru C, Hoffmann JA, Imler JL
Abstract : The response of drosophila to bacterial and fungal infections involves two signaling pathways, Toll and Imd, which both activate members of the transcription factor NF-kappaB family. Here we have studied the global transcriptional response of flies to infection with drosophila C virus. Viral infection induced a set of genes distinct from those regulated by the Toll or Imd pathways and triggered a signal transducer and activator of transcription (STAT) DNA-binding activity. Genetic experiments showed that the Jak kinase Hopscotch was involved in the control of the viral load in infected flies and was required but not sufficient for the induction of some virus-regulated genes. Our results indicate that in addition to Toll and Imd, a third, evolutionary conserved innate immunity pathway functions in drosophila and counters viral infection.
| Nature Immunology
2005: Vol 6, 646-953 | Abstract
Article complet | New insights into Drosophila larval hemocyte functions through genome-wide analysis
Irving P, Ubeda JM, Doucet D, Troxler L, Lagueux M, Zachary D, Hoffmann JA, Hetru C, Meister M
Abstract : Drosophila blood cells or haemocytes comprise three cell lineages, plasmatocytes, crystal cells and lamellocytes, involved in immune functions such as phagocytosis, melanisation and encapsulation. Transcriptional profiling of activities of distinct haemocyte populations and from naive or infected larvae, was performed to find genes contributing to haemocyte functions. Of the 13 000 genes represented on the microarray, over 2500 exhibited significantly enriched transcription in haemocytes. Among these were genes encoding integrins, peptidoglycan recognition proteins (PGRPs), scavenger receptors, lectins, cell adhesion molecules and serine proteases. One relevant outcome of this analysis was the gain of new insights into the lamellocyte encapsulation process. We showed that lamellocytes require betaPS integrin for encapsulation and that they transcribe one prophenoloxidase gene enabling them to produce the enzyme necessary for melanisation of the capsule. A second compelling observation was that following infection, the gene encoding the cytokine Spatzle was uniquely upregulated in haemocytes and not the fat body. This shows that Drosophila haemocytes produce a signal molecule ready to be activated through cleavage after pathogen recognition, informing distant tissues of infection.
| Cellular Microbiology
2005: Vol 7, 335-350 | Abstract
Article complet | Sensing and Signaling during Infection in Drosophila
Royet J, Reichhart JM, Hoffmann JA
Abstract : Most of the progress in dissecting the Drosophila antimicrobial response over the past decade has centered around intracellular signaling pathways in immune response tissues and expression of genes encoding antimicrobial peptide genes. The past few years, however, have witnessed significant advances in our understanding of the recognition of microbial invaders and subsequent activation of signaling cascades. In particular, the roles of peptidoglycan recognition proteins, which have known homologues in mammals, have been recognized and examined at the structural and functional levels.
| Current Opinion in Immunology
2005: Vol 17, 11-17 | Abstract
Article complet | Eater, a transmembrane protein mediating phagocytosis of bacterial pathogens in Drosophila
Kocks C, Cho JH, Nehme N, Ulvila J, Pearson AM, Meister M, Strom C, Conto SL, Hetru C, Stuart LM, Stehle T, Hoffmann JA, Reichhart JM, Ferrandon D, Ramet M, Ezekowitz RA
Abstract : Phagocytosis is a complex, evolutionarily conserved process that plays a central role in host defense against infection. We have identified a predicted transmembrane protein, Eater, which is involved in phagocytosis in Drosophila. Transcriptional silencing of the eater gene in a macrophage cell line led to a significant reduction in the binding and internalization of bacteria. Moreover, the N terminus of the Eater protein mediated direct microbial binding which could be inhibited with scavenger receptor ligands, acetylated, and oxidized low-density lipoprotein. In vivo, eater expression was restricted to blood cells. Flies lacking the eater gene displayed normal responses in NF-kappaB-like Toll and IMD signaling pathways but showed impaired phagocytosis and decreased survival after bacterial infection. Our results suggest that Eater is a major phagocytic receptor for a broad range of bacterial pathogens in Drosophila and provide a powerful model to address the role of phagocytosis in vivo.
| Cell
2005: Vol 123, 335-346 | Abstract
Article complet | Sensing infection in Drosophila: Toll and beyond
Ferrandon D, Imler JL, Hoffmann JA
Abstract : Drosophila has evolved a potent immune system that is somewhat adapted to the nature of infections through the selective activation of either one of two NF-kappaB-like signalling pathways, the Toll and IMD (Immune deficiency) pathways. In contrast to the mammalian system, the Toll receptor does not act as a pattern recognition receptor (PRR) but as a cytokine receptor. The sensing of microbial infections is achieved by at least four PRRs that belong to two distinct families: the peptidoglycan recognition proteins (PGRPs) and the Gram-negative binding proteins (GNBPs)/beta-glucan recognition proteins (betaGRPs).
| Semin. Immunol.
2004: Vol 16, 43-53. | Abstract
Article complet | Primitive Immune Systems
Hoffmann JA
Abstract : This volume of Immunological Reviews is devoted to primitive immune systems. Of course, since what is primitive is in the eye of the beholder, we must first define what constitutes the primitive immune system. The expression ante-antibody immunity, coined by Alan Ezekowitz, describes the present topic well. As antibodies did not appear in evolution before the separation of the ancestors of jawless and jawed fish, that is some 450 million years ago, ante-antibody immunity is indeed the ancient and first (primus) form of immunity, and it will serve as our operating definition for this volume.
| Immunological Reviews
2004: Vol 198, 5-9 | Abstract
Article complet | Role of Drosophila pattern recognition receptor, PGRP-SD, in detection of Gram-positive bacteria
Bischoff V, Vignal C, Boneca T, Michel T, Hoffmann JA, Royet J
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.
| Nature Immunology
2004: Vol 5, 1175-1180 | Abstract
Article complet | Toll-dependent and Toll-independent immune response in Drosophila
Imler JL, Ferrandon D, Royet J, Reichhart JM, Hetru C, Hoffmann JA
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.
| Journal of Endotoxin Research
2004: Vol 10, 241-246 | Abstract
Article complet | Peptidomic and Proteomic Analyses of the Systemic Immune Response of Drosophila
Levy F, Rabel D, Charlet M, Bulet P, Hoffmann JA, Ehret-Sabatier L
Abstract : Insects have developed an efficient host defense against microorganisms, which involves humoral and cellular mechanisms. Numerous data highlight similarities between defense responses of insects and innate immunity of mammals. The fruit fly, Drosophila melanogaster,isa favorable model system for the analysis of the first line defense against microorganisms. Taking advantages of improvements in mass spectrometry (MS), two-dimensional (2D) gel electrophoresis and bioinformatics, differential analyses of blood content (hemolymph) from immune-challenged versus control Drosophila were performed. Two strategies were developed: (i) peptidomic analyses through matrixassisted laser desorption/ionization time-of-flight (MALDI-TOF) MS and high performance liquid chromatography for molecules below 15 kDa, and (ii) proteomic studies based on 2D gel electrophoresis, MALDI-TOF fingerprinting and database searches, for compounds of greater molecular masses. The peptidomic strategy led to the detection of a large number of peptides induced in the hemolymph of challenged flies as compared to controls. Of these, 28 were characterized, amongst which were antimicrobial peptides. The 2Dgel electrophoresis strategy led to the detection of 70 spots differentially regulated by at least fivefold after microbial infection. This approach yielded the identity of a series of proteins that were related to the Drosophila immune response, such as proteases, protease inhibitors, prophenoloxydase-activating enzymes, serpins and a Gram-negative binding protein-like protein. This strategy also brought to light new candidates with a potential function in the immune response (odorant-binding protein, peptidylglycine a-hydroxylating monooxygenase and transferrin). Interestingly, several molecules resulting from the cleavage of proteins were detected after a fungal infection. Together, peptidomic and proteomic analyses represent new tools to characterize molecules involved in the innate immune reactions of Drosophila.
| Biochimie
2004: Vol 86, 607-616 | Abstract
Article complet | Toll signalling: the TIReless quest for specify
Imler JL, Hoffmann J
Abstract : Toll-like receptors (TLRs) have an essential role in the innate immune response against microbial pathogens. These receptors are characterized by an ectodomain composed of leucine-rich repeats, and an intracytoplasmic domain conserved in members of the interleukin-1 receptor (IL-1R) family (Toll/IL or TIR domain). Mammalian TLRs are now recognized as primordial receptors of innate immunity mediating activation by peptidoglycan and bacterial lipopeptides (TLR2), lipopolysaccharide (LPS, TLR4), double-standed (ds) RNA (TLR3), flagellin (TLR5) and unmethylated CpG DNA motifs (TLR9). Upon stimulation, TLRs activate the transcription NF-kB and AP1, leading to production of inflammatory cytokines such as tumor necrosis factor (TNF)-a and up-regulation of the costimulatory molecules CD80 and CD86 on dentritic cells (DCs). The diversity of microbial molecular patterns activating specific TLRs contrasts with the apparent uniformity of the reponses induced by these receptors. However, recent results indicate that signaling by TLRs is more complex that initially anticiped, and that a panel of intracytoplasmic adapter molecules may mirror the diversity of extracellular stimuli for TLRs. In this issue of Nature Immunology and in a recently published article, a new adapter protein involved in TLR signaling has been identified.
| Nature Immunology
2003: Vol 4, 105-106 | Abstract
Article complet | Virulence factors of the human opportunistic pathogen Serratia marcescens identified by in vivo screening
Kurz CL, Chauvet S, Andres E, Aurouze M, Vallet I, Michel GP, UH M, Celli J, Filloux A, DE Bentzmann S, Steinmetz I, Hoffmann JA, Finlay BB, Gorvel JP, Ferrandon D, Ewbank JJ
Abstract : The human opportunistic pathogen Serratia marcescens is a bacterium with a broad host range, and represents a growing problem for public health. Serratia marcescens kills Cenorhabditis elegans after colonizing the nematode’s interstine. We used C. elegans to sreen a bank of transposon-induced S. marcescens mutants and isolated 23 clones with an attenuated virulence. Nine of the selected bacterial clones also showed a reduced virulence in an insect model of infection. Of these, three exhibited a reduced cytotoxicity in vitro, and among them one was also markedly attenuated in its virulence in a murine lung infection model. For 21 of the 23 mutants, the transposon insertion site was identified. This revealed that among the genes necessary for full in vivo virulence are those that function in lipopolysachharide (LPS) biosynthesis , iron uptake and hemolysin production. Using this system we also identified novel conserved virulence factors required for Pseudomonas aeruginosa pathogenicity. This study extends the utility of C. elegans as an in vivo model for the study of basterial virulence and advances the molecular understanding of S. marcescens pathogenicity.
| EMBO J.
2003: Vol 22, 1451-1460 | Abstract
Article complet | Drosophila melanogaster antimicrobial defense. In "J. Infectious Disease:Innate Immunity"
Hetru C, Troxler L, Hoffmann JA
Abstract : The Drosophila melanogaster host defense is complex but remarkably efficient. It is a multifaceted response to a variety of fungal, bacterial, and parasitic invaders. Current knowledge is discussed on recognition of infectious microorganisms and on the activation of intracellular signaling cascades that accur with the expression of numerous immune-responsive genes, among which, to date, the most prominent appear to encode potent antimicrobial peptides.
| Ezekowitz R.A.B. and Hoffmann J.A., eds. Humana Press Inc, Totowa
2003: 187 Suppl 2 :S327-34 | Abstract
Article complet | Binding of the Drosophila cytokine Spaetzle to Toll is direct and establishes signaling
Weber AN, Tauszig-Delamasure S, Hoffmann JA, Lelievre E, Gascan H, Ray KP, Morse MA, Imler JL, Gay NJ
Abstract : The extracellular protein Spatzle is required for activation of the Toll signaling pathway in the embryonic development and innate immune defense of Drosophila. Spatzle is synthetized as a pro-protein and is processed to a functionnal form by a serine protease. We show here that the mature form of Spatzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. Spatzle specifically bound to Drosophila cells and to Cos-7 cells expressing Toll. Furthermore, in vitro experiments showed that the mature form of Spatzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one Spatzle dimer to two receptors. The Spatzle pro-protein was inactive in all these assays, indicating that the pro-domains sequence, which is natively unstructed, 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.
| Nature Immunology
2003: Vol 4, 794-800 | Abstract
Article complet | The Immune Response of Drosophila
Hoffmann JA
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.
| Nature
2003: Vol 426, 33-38 | Abstract
Article complet | Spheniscins : avian b-defensins in preserved stomach contents of the king penguin, Aptenodytes patagonicus
Thouzeau C, Le Maho Y, Froget G, Sabatier L, Le Bohec C, Hoffmann JA, Bulet P
Abstract : During the last part of egg incubation in king penguins, the male can preserve undigested food in the stomach for several weeks. This ensures survival of the newly hatched chick, in cases where the return of the foraging female from the sea is delayed. In accordance with the characterization of stress-induced bacteria, we demonstrate the occurrence of strong antimicrobial activities in preserved stomach contents. We isolated and fully characterized two isoforms of a novel 38-residue antimicrobial peptide (AMP), spheniscin, belonging to the beta-defensin subfamily. Spheniscin concentration was found to strongly increase during the period of food storage. Using a synthetic version of one of the two spheniscin isoforms, we established that this peptide has a broad activity spectrum, affecting the growth of both pathogenic bacteria and fungi. Altogether, our data suggest that spheniscins and other, not yet identified, antimicrobial substances may play a role in the long-term preservation of stored food in the stomach of king penguins.
| J. Biol. Chem.
2003: Vol 278, 51053-51058 | Abstract
Article complet | Dual activation of the Drosophila toll pathway by two pattern recognition receptors
Gobert V, Gottar M, Matskevich AA, Rutschmann S, Royet J, Belvin M, Hoffmann JA, Ferrandon D
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.
| Science
2003: Vol 302, 2126-2130 | Abstract
Article complet | Drosophila innate immunity: an evolutionary perspective
Hoffmann JA, Reichhart JM
Abstract : In response to microbial infections, Drosophila mounts a multifaceted immune response involving humoral reactions that culminate in the destruction of invading organismes 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 hre evolutionary perspectives on our present understanding of the antimicrobial defenses of Drosophila.
| Nat Immunol.
2002: Vol 3, 121-126. | Abstract
Article complet | Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections
Tauszig-Delamasure S, Bilak H, Capovilla M, Hoffmann JA, Imler JL
Abstract : We report here the identification and funtional characterization of DmMyD88, a gene encoding the Drosophila homolog of mammalian MyD88. DmMyD88 combines a Toll- IR hology (TIR) domain and death domain. Overexpression of DmMyD88 was sufficient to induce expression of the antifongal 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 comparaison of DmMyD88-mutant flies and MyD88-deficient mice showed essential differences in the control of Gram-negative infection in insects and mammals.
| Nat Immunol.
2002: Vol 3, 91-97. | Abstract
Article complet | The Drosophila response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein
Gottar M, Gobert V, Michel, T Belvin M, Duyk G, Hoffmann JA, Ferrandon D, Royet J
Abstract : The antimicrobial defence of Drosophila relies largely on the challenge-induced symptômes of an array of potent antimicrobial peptides by the fat body. The defence against Gram-positive bacteria and natural fungal infections is mediated by the Toll signalling pathway, whereas defence against Gram-negative bacteria is dépendent on the Immune deficiency (IMD) pathway. Loss-of-function mutations in either pathway reduce the resistance to corresponding infections. The link betterave microbial infections and activation of these two pathways has remained elusive. The Toll pathway is activated by Gram-positive bacteria through a circulating Peptidoglycan recognition protein (PGRP-SA). PGRPs appear to be highly conserved from insects to mammals, and the Drosophila genome contains 13 members. Here we report a mutation in a gene coding for a putative transmembrane protéine, PGRP-LC, which reduces survival to Gram-negative sepsis but has no effect on the response to Gram-positive bacteria or natural fungal infections. By genetic épistasies, we demonstrate that PGRP-LC acts upstream on the imd gene. The data on PGRP-SA with respect to the response to Gram-positive infections, together with the present report, indicate that the PGRP family has a principal role in sensing microbial infections in Drosophila.
| Nature
2002: Vol 416, 640-644. | Abstract
Article complet | Toll receptors in Drosophila: a family of molecules regulating development and immunity
Imler JL, Hoffmann JA
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.
| Current Topic Microbiol. Immunol.
2002: Vol 270, 63-79. | Abstract
Article complet | Activation of Drosophila Toll during fungal infection by a blood serine protease
Ligoxygakis P, Pelte N, Hoffmann J, Reichhart JM
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 endodes a previously unknown serine protease, block induction on the Tollpathway by fungi and resistance to this type of infection.
| Science
2002: Vol 297, 114-116. | Abstract
Article complet | The Drosophila Immune Defense against Gram-Negative Infection Requires the Death Protein dFADD
Naitza S, Rossé C, Kappler C, Georgel P, Belvin M, Gubb D, Camonis J, Hoffmann J, Reichhart JM
Abstract : Drosophila responds to Gram-negative infections by mounting an immune response that depends on components of the IMD pathway. We recently showed that imd encodes a protein with a death domain with high similitary to that of mammalian RIP. Using a two-hybrid screen in yeast, we have isolated the death protein dfADD as a molecule that associates with IMD. Our data show that loss of dfADD function renders flies highly susceptible to Gram-negative infections without affecting resistance to Gram-positive bacteria. By genetic analysis we show that dfADD acts downstream of IMD in the pathway that controls inducibility of the antibacterial peptide genes.
| Immunity
2002: Vol 17, 575-581 | Abstract
Article complet | Notch Signaling Controls Lineage Specification during Drosophila Larval Hematopoiesis
Duvic B, Hoffmann J, Meister M, Royet J
Abstract : Drosophila larval hemocytes originate from a hematopoietic organ called lymph glands, which are composed of paired lobes located along the dorsal vessel. Two nature blood cell populations are found in the circulating hemolymph : the macrophage-like plasmatocytes, and the crystal cells that contain enzymes of the immune-related melanization process. A third class of cells, called lamellocytes, are normally absent in larvae but differentiate after infection by parasites too large to be phagocytosed. Here we present evidence that the Notch signaling pathway plays an instructive role in the differentiation of crystal cells. Loss-of-function mutations in Notch result in severely decreased crystal cell numbers, whereas overexpression of Notch provokes the differentiation of high numbers of these cells. We demonstrate that, in this process, Serrate, not Delta, is the Notch ligand. In addition, Notch function is necessary for lamellocyte proliferation upon parasitization, although Notch overexpression does not result in lamellocyte production. Finally, Notch does not appear to play a role in the differentiation of the plasmatocyte lineage. This study underlines the existence of parallels in the genetic control of hematopoiesis in Drosophila and in mammals.
| Current Biology
2002: Vol 12, 1923-1927. | Abstract
Article complet | PVF2, a PDGF/VEGF-like growth factor, induces hemocyte proliferation in Drosophila larvae
Munier A-I, Doucet D, Perrodou E, Zachary D, Meister M, Hoffmann J, Janeway CA, Lagueux M
Abstract : Blood cells play a crucial role in both morphogenetic and immunological processes in Drosophila, yet the factors regulating their proliferation remain largely unknown. In order to address this question, we raised antibodies against a tumorous blood cell line and identified an antigenic determinant that marks the surface of phenotypes and also circulating plasmotocytes in larvae. This antigen was identified as a Drosophila homolog of the mammalian receptor for plateletderived growth factor (PDGF)/vascular endothelial growth factor (VEGF). The Drosophila receptor controls cell proliferation in vitro. By overexpressing in vivo one of its putative ligands, PVF2, we included a dramatic increase in circulating hemocytes. These results identify the PDGF/VEGF receptor homolog and one of its ligands as important player in Drosophila hematopoiesis.
| EMBO Rep.
2002: Vol 3, 1195-1200. | Abstract
Article complet | Immunity-related genes and gene families in Anopheles gambiae
Christophides GK, Zdobnov E, Barillas-Mury C, Birney E, Blandin S, Blass C, Brey PT, Collins FH, Danielli A, Dimopoulos G, Hetru C, Hoa NT, Hoffmann JA, Kanzok SM, Letunic I, Levashina EA, Loukeris TG, Lycett G, Meister S, Michel K, Moita LF, Muller HM, Osta MA, Paskewitz SM, Reichhart JM, Rzhetsky A, Troxler L, Vernick KD, Vlachou D, Volz J, von Mering C, Xu J, Zheng L, Bork P, Kafatos FC
Abstract : We have identified 242 Anopheles gambiae genes from 18 gene families implicated in innate immunity and have detected marked diversification relative to Drosophila melanogaster. Immune-related gene families involved in recognition, signal modulation, and effector systems show a marked deficit of orthologs and excessive gene expansions, possibly reflecting selection pressures from different pathogens encountered in these insects' very different life-styles. In contrast, the multifunctional Toll signal transduction pathway is substantially conserved, presumably because of counterselection for developmental stability. Representative expression profiles confirm that sequence diversification is accompanied by specific responses to different immune challenges. Alternative RNA splicing may also contribute to expansion of the immune repertoire.
| Science
2002: Vol 298, 159-165. | Abstract
Article complet | Tissue and stage-specific expression of the Tolls in Drosophila embryos
Kambris Z, Hoffmann JA, Imler JL, Capovilla M
Abstract : The Drosophila transmembrane receptor Toll play 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 characterizated Toll (Toll-1) and 18-wheller (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.
| Gene Expression Patterns
2002: Vol 2, 311-317. | Abstract
Article complet | A serpin mutant links Toll activation to melanization in the host defence of Drosophila
Ligoxygakis P, Pelte N, Ji C, Leclerc V, Duvic B, Belvin M, Jiang H, Hoffmann JA, Reichhart JM
Abstract : A prominent response during the Drosophila host defence is the introduction 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 ant the melanization reaction has not been family established. Here, we present evidence for the coordination of hemolymp-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.
| EMBO J
2002: Vol 21, 6330-6337. | Abstract
Article complet | A genome-wide analysis of immune responses in Drosophila
Irving P, Troxler L, Heuer TS, Belvin M, Kopczynski C, Reichhart JM, Hoffmann JA, Hetru C
Abstract : Oligonucleotide DNA microarrays were used for a genome-wide analysis of immune-challenged Drosophila infected with Gram-positive or Gram-negative bacteria, or with fungi. Aside from the expression of an established sef of immune defense genes, a significant number of previously unseen immune-induced genes were found. Genes of particular interest include corin- and Stubble-like genes, both of which have a type II transmembrane domain, easter- and snake-like genes, which may fulfil the roles of easter and snake in the Toll pathway, and a masque rade-like gene, potentially involved in enzyme regulation. The miccroarray data has also helped to greatly reduce the number of target genes in large gene groups, such as the proteases, helping to direct the choices for future mutant studies. Many of the up-regulated genes fit into the current conceptual framework of host defense, whereas others, including the sustantial number of genes with unknown functions, offer new avenues for research.
| Proc. Natl. Acad. Sci. USA
2001: Vol 98, 15119-15224. | Abstract
Article complet | Insect Immunity. Constitutive expression of a cysteine-rich antifungal and a linear antibacterial peptide in a termite insect
Lamberty M, Zachary D, Lanot R, Bordereau C, Robert A, Hoffmann JA, Bulet P
Abstract : Two novel antimicrobial peptides, which we propose to name termicin and spinigerin, have been isolated from the fungus-growing termite Pseudacanthotermes spiniger (heterometabole insect, Isoptera). Termicin is a 36-amino acid residue antifungal peptide, with six cysteines arranged in a disulfide array similar to that of insect defensins. In contrast to most insect defensins, termicin is C-terminally amidated. Spinigerin consists of 25 amino acids and is devoid of cysteines. It is active against bacteria and fungi. Termicin and spinigerin show no obvious sequence similarities with other peptides. Termicin is constitutively present in hemocyte granules and in salivary glands. The presence of termicin and spinigerin in unchallenged termites contrasts with observations in evolutionary recent insects or insects undergoing complete metamorphosis, in which antimicrobial peptides are induced in the fat body and released into the hemolymph after septic injury.
| J. Biol Chem.
2001: Vol 276, 4085-4092. | Abstract
Article complet | LPS-induced immune response in Drosophila
Imler JL, Tauszig S, Jouanguy E, Forestier C & Hoffmann JA
Abstract : The study of the regulation of the inducible synthesis of antimicrobial peptides in Drosophila melanogaster has established this insect as a powerful model in which to study innate immunity. In particular, the molecular characterization of the regulatory pathway controlling the antifungal peptide drosomycin has revealed the importance of Tool receptors in innate immunity. We report here that injection of LPS into flies induces an immune response, suggesting that LPS receptors are used in Drosophila to detect Gram-negative bacteria infection. We have identified in the recently sequenced genome of Drosophila eight genes coding for Toll-like receptors in addition to Toll, which may function as LPS receptors. However, overexpression of a selection of these genes in tissue-culture cells does not result in up-regulation of the antibacterial peptide genes. These results are discussed in light of the recent data from genetic screens aimed at identifying the genes controlling the antibacterial response in Drosophila.
| J. Endotox. Res.
2001: Vol 6, 459-462 | Abstract
Article complet | Toll receptors in innate immunity
Imler JL & Hoffmann JA
Abstract : Innate immunity is the first-line host defence of multicellular organisms that rapidly operates to limit infection upon exposure to infectious agents. In addition, the cells and molecules operating during this early stage of the immune response in vertebrates have a decisive impact on the shaping of the subsequent adaptive response. Genetic studies initially carried in the fruitfly Drosophila and later in mice have revealed the importance of proteins of the Toll family in the innate immune response. We present here our current understanding of the role of this evolutionary ancient family of proteins which are thought to function as cytokine receptor (Toll in Drosophila) or pattern recognition receptor (TLRs in mammals) and activate similar, albeit non identical, signal transduction pathways in flies and mammals.
| Trends in Cell Biol
2001: Vol 11, 304-310 | Abstract
Article complet | Gambicin: a novel immune responsive antimicrobial peptide from the malaria vector Anopheles gambiae
Vizioli J, Bulet P, Hoffmann JA, Kafatos FC, Muller HM, Dimopoulos G
Abstract : A novel mosquito antimicrobial peptide, gambicin, and the corresponding gene were isolated in parallel through differential display-PCR, an expressed sequence tag (EST) project, and characterization of an antimicrobial activity in a mosquito cell line by reverse-phase chromatography. The 616-bp gambicin ORF encodes an 81-residue protein that is processed and secreted as a 61-aa mature peptide containing eight cysteines engaged in four disulfide bridges. Gambicin lacks sequence homology with other known proteins. Like other Anopheles gambiae antimicrobial peptide genes, gambicin is induced by natural or experimental infection in the midgut, fatbody, and hemocyte-like cell lines. Within the midgut, gambicin is predominantly expressed in the anterior part. Both local and systemic gambicin expression is induced during early and late stages of natural malaria infection. In vitro experiments showed that the 6.8-kDa mature peptide can kill both Gram-positive and Gram-negative bacteria, has a morphogenic effect on a filamentous fungus, and is marginally lethal to Plasmodium berghei ookinetes. An oxidized form of gambicin isolated from the cell line medium was more active against bacteria than the nonoxidized form from the same medium.
| Proc. Natl. Acad. Sci. USA
2001: Vol 98, 12630-12635. | Abstract
Article complet | Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis
Georgel P, Naitza S, Kappler C, Ferrandon D, Zachary D, Swimmer C, Kopczynski C, Duyk G, Reichhart JM, Hoffmann JA
Abstract : We report the molecular characterization of the immune deficiency (imd) gene, which encodes a protein with a death domain similar to that of mammalian RIP (receptor interacting protein), a protéine that plays a role in both NF- B activation and apoptosis. We show that imd functions upstream of the DmIKK signalosome and the caspase DREDD in the control of antibacterial peptides genes. Strikingly, overexpression of imd leads to constitutive transcription of these genes and to apoptosis, and both effects are blocked by coexpression of the caspase inhibitor P35. We also show that imd is involved in the apoptotic response to UV irradiation. These data raise the possibility that antibacterial response and apoptosis share common control eléments in Drosophila.
| Dev. Cell
2001: Vol 1, 503-514 | Abstract
Article complet | Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein
Michel T, Reichhart JM, Hoffmann JA, Royet J
Abstract : Microbial infection activates two distinct intracellular signalling cascades in the immune-responsive fat body of Drosophila. Gram-positive bacteria and fungi predominatly induce the Toll signalling pathway, whereas Gram-negative bacteria activate the Imd pathway. Loss-of-function mutants in either pathway reduce the resistance to corresponding infections. Genetic screens have identified a range of genes involved in these intracellular signalling cascades, but how they are activated by microbial infection is largely unknown. Activation of the transmembrane receptor Toll requires a proteolytically cleaved form of an extracellular cytokine-like polypeptide, Spätzle, suggesting that Toll does not itself function as a bona fide recognition receptor of microbial patterns. This is a apparent contrast with the mammalian Toll-like receptors and raises the question of which host molecules actually rencognize microbial patterns to activate Toll through Spätzle. Here we present a mutation that blocks Toll activation by Gram-positive bacteria and significantly decreases resistance to this type of infection. The mutation semmelweis (seml) inactivates the gene encoding a peptidoglycan recognition protein (PGRP-SA). Interestingly, seml does not affect Toll activation by fungal infection, indicating the existence of a distinct recognition system for fungi to activate the Toll pathway.
| Nature
2001: Vol 414, 756-759. | Abstract
Article complet | L'immunité innée : de la drosophile à l'homme
Ferrandon D, Hetru C, Reichhart JM & Hoffmann JA
Abstract : No abstract.
| Pour la Science: "Les défenses de l'organisme 8-12"
Dossier Hors-Série, Octobre 2000 | Abstract
Article complet | The antimicrobial host defense of Drosophila
Meister M, Hetru C & Hoffmann JA
Abstract : No abstract
| Curr. Topics in Microbiol. and Immunol.
2000: 248 17-36 | Abstract
Article complet | Signaling mechanisms in the antimicrobial host defense of Drosophila
Imler JL & Hoffmann JA
Abstract : Drosophila has appeared in recent years as a powerful model to study innate immunity. Several papers published in the past year shed light on the role of the three Rel proteins Dorsal, Dif and Relish in the regulation of antimicrobial peptide expression. In addition, the discovery that a blood serine protease inhibitor is involved in the control of the antifungal response indicates that Toll is activated upon triggering of a proteolytic cascade and does not function as a Drosophila pattern recognition receptor.
| Curr. Opin. in Microbiol.
2000: 3, 16-22 | Abstract
Article complet | Cloning and analysis of a cecropin gene from the malaria vector mosquito, Anopheles gambiae
Vizioli J, Bulet P, Charlet M, Lowenberger C, Blass C, Müller HM, Dimopoulos G, Hoffmann JA, Kafatos FC & Richman A
Abstract : Parasites of the genus Plasmodium are transmitted to mammalian hosts by anopheline mosquitoes. Within the insect vector, parasite growth and development are potentially limited by antimicrobial defence molecules. Here, we describe the isolation of cDNA and genomic clones encoding a cecropin antibacterial peptide from the malaria vector mosquito Anopheles gambiae. The locus was mapped to polytene division 1C of the X chromosome. Cecropin RNA was induced by infection with bacteria and Plasmodium. RNA levels varied in different body parts of the adult mosquito. During development, cecropin expression was limited to the early pupal stage. The peptide was purified from both adult mosquitoes and cell culture supernatants. Anopheles gambiae synthetic cecropins displayed activity against Gram-negative and Gram-positive bacteria, filamentous fungi and yeasts.
| Insect Mol. Biol.
2000: 9, 75-84 | Abstract
Article complet | The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila
Rutschmann S, Jung AC, Hetru C, Reichhart JM, Hoffmann JA & Ferrandon D
Abstract : We have isolated two Drosophila lines that carry point mutations in the gene coding for the NF-KB-like factor DIF. Like mutants of the Toll pathway, Dif mutant flies are susceptible to fungal but not to bacterial infections. Genetic epistasis experiments demonstrate that Dif mediates the Toll-dependent control of the inducibility of the antifungal peptide gene Drosomycin. Strikingly, DIF alone is required for the antifungal response in adults, but is redundant in larvae with Dorsal, another Rel family member. In Drosophila, Dif appears to be dedicated to the antifungal defense elicited by fungi and gram-positive bacteria. We discuss in this light the possibility that NF-KB1/p50 might be required more specifically in the innate immune response against gram-positive bacteria in mammals.
| Immunity
2000: 12, 569-580 | Abstract
Article complet | Androctonin, a hydrophilic disulphide-bridged non-haemolytic antimicrobial peptide : a plausible mode of action
Hetru C, Letellier L, Oren Z, Hoffmann JA & Shai Y
Abstract : Androctonin is a 25-residue non-haemolytic anti-microbial peptide isolated from the scorpion Androctonus australis and contains two disulphide bridges. Androctonin is different from known native anti-microbial peptides, being a relatively hydrophilic and non-amphipathic molecule. This raises the possibility that the target of androctonin might not be the bacterial membrane, shown to be a target for most amphipathic lytic peptides. To shed light on its mode of action on bacteria and its non-haemolytic activity, we synthesized androctonin, its fluorescent derivatives and its all-D-amino acid enantiomer. The enantiomer preserved high activity, suggesting a lipid-peptide interaction between androctonin and bacterial membranes. In Gram-positive and (at higher concentrations) Gram-negative bacteria, androctonin induced an immediate perturbation of the permeability properties of the cytoplasmic membrane of the bacterial energetic state, concomitant with perturbation of the morphology of the cell envelope as revealed by electron microscopy. Androctonin binds only to negatively charged lipid vesicles and induces the leakage of markers at high concentrations and with a slow kinetics, in contrast with amphipathic alpha-helical anti-microbial peptides that bind and permeate negatively charged vesicles, and to a smaller extent also zwitterionic ones. This might explain the selective lytic activity of androctonin towards bacteria but not red blood cells. Polarized attenuated total reflection-Fourier transform infrared spectroscopy revealed that androctonin adopts a beta-sheet structure in membranes and did not affect the lipid acyl chain order, which supports a detergent-like effect. The small size of androctonin, its hydrophilic character and its physicochemical properties are favourable features for its potential application as a replacement for commercially available antibiotics to which bacteria have developed resistance.
| Biochem. J.
2000: 345, 653-664 | Abstract
Article complet | The phytopathogenic bacteria Erwinia carotovora infects Drosophila and activates an immune response
Basset A, Khush RS, Braun A, Gardan L, Boccard F, Hoffmann JA & Lemaitre B
Abstract : Although Drosophila possesses potent immune responses, little is known about the microbial pathogens that infect Drosophila. We have identified members of the bacterial genus Erwinia that induce the systemic expression of genes encoding antimicrobial peptides in Drosophila larvae after ingestion. These Erwinia strains are phytopathogens and use flies as vectors, our data suggest that these strains have also evolved mechanisms for exploiting their insect vectors as hosts. Erwinia infections induce an antimicrobial response in Drosophila larvae with a preferential expression of antibacterial versus antifungal peptide-encoding genes. Antibacterial peptide gene expression after Erwinia infection is reduced in two Drosophila mutants that have reduced numbers of hemocytes, suggesting that blood cells play a role in regulating Drosophila antimicrobial responses and also illustrating that this Drosophila-Erwinia interaction provides a powerful model for dissecting host-pathogen relationships.
| Proc. Natl. Acad. Sci. USA
2000: 97, 3376-3381 | Abstract
Article complet | Toll-related receptors and the control of antimicrobial peptide expression in Drosophila
Tauszig S, Jouanguy E, Hoffmann JA & Imler JL
Abstract : Insects defend themselves against infectious microorganisms by synthesizing potent antimicrobial peptides. Drosophila has appeared in recent years as a favorable model to study this innate host defense. A genetic analysis of the regulation of the antifungal peptide drosomycin has demonstrated a key role for the transmembrane receptor Toll, which prompted the search for mammalian homologs. Two of these, Toll-like receptor (TLR)2 and TLR4, recently were shown to play a critical role in innate immunity against bacteria. Here we describe six additional Toll-related genes (Toll-3 to Toll-8) in Drosophila in addition to 18-wheeler. Two of these genes, Toll-3 and Toll-4, are expressed at a low level. Toll-6, -7, and -8, on the other hand, are expressed at high levels during embryogenesis and molting, suggesting that, like Toll and 18w, they perform developmental functions. Finally, Toll-5 is expressed only in larvae and adults. By using chimeric constructs, we have tested the capacity of the signaling Toll/IL-1R homology domains of these receptors to activate antimicrobial peptide promoters and found that only Toll and Toll-5 can activate the drosomycin promoter in transfected cells, thus demonstrating specificity at the level of the Toll/IL-1R homology domain. In contrast, none of these constructs activated antibacterial peptide promoters, suggesting that Toll-related receptors are not involved in the regulation of antibacterial peptide expression. This result was independently confirmed by the demonstration that a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide.
| Proc. Natl. Acad. Sci. USA
2000: 97, 10520-10525 | Abstract
Article complet | Role of Drosophila IKKg in a Toll-independent antibacterial immune response
Rutschmann S, Jung AC, Zhou R, Silverman N, Hoffmann JA & Ferrandon D
Abstract : We have generated, by ethylmethane sulfonate mutagenesis, loss-of-function mutants in the Drosophila homolog of the mammalian I-kappa B kinase (IKK) complex component IKK gamma (also called NEMO). Our data show that Drosophila IKK gamma is required for the Relish-dependent immune induction of the genes encoding antibacterial peptides and for resistance to infections by Escherichia coli. However, it is not required for the Toll-DIF-dependent antifungal host defense. The results indicate distinct control mechanisms of the Rel-like transactivators DIF and Relish in the Drosophila innate immune response and show that Drosophila Toll does not signal through a IKK gamma-dependent signaling complex. Thus, in contrast to the vertebrate inflammatory response, IKK gamma is required for the activation of only one immune signaling pathway in Drosophila.
| Nature Immunol.
2000: 1, 342-347 | Abstract
Article complet | Constitutive expression of a complement-like protein in Toll and JAK gain-of-function mutants of Drosophila
Lagueux M, Perrodou E, Levashina EA, Capovilla & Hoffmann JA
Abstract : We show that Drosophila expresses four genes encoding proteins with significant similarities with the thiolester-containing proteins of the complement C3/alpha(2)-macroglobulin superfamily. The genes are transcribed at a low level during all stages of development, and their expression is markedly up-regulated after an immune challenge. For one of these genes, which is predominantly expressed in the larval fat body, we observe a constitutive expression in gain-of-function mutants of the Janus kinase (JAK) hop and a reduced inducibility in loss-of-function hop mutants. We also observe a constitutive expression in gain-of-function Toll mutants. We discuss the possible roles of these novel complement-like proteins in the Drosophila host defense.
| Proc. Natl. Acad. Sci. USA
2000: 97, 11427-11432 | Abstract
Article complet | Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia
Tzou P, Ohresser S, Ferrandon D, Capovilla M, Reichhart JM, Lemaitre B, Hoffmann JA & Imler JL
Abstract : The production of antimicrobial peptides is an important aspect of host defense in multicellular organisms. In Drosophila, seven antimicrobial peptides with different spectra of activities are synthesized by the fat body during the immune response and secreted into the hemolymph. Using GFP reporter transgenes, we show here that all seven Drosophila antimicrobial peptides can be induced in surface epithelia in a tissue-specific manner. The imd gene plays a critical role in the activation of this local response to infection. In particular, drosomycin expression, which is regulated by the Toll pathway during the systemic response, is regulated by imd in the respiratory tract, thus demonstrating the existence of distinct regulatory mechanisms for local and systemic induction of antimicrobial peptide genes in Drosophila.
| Immunity
2000: Vol 13, 737-748 | Abstract
Article complet | Toll and Toll-like proteins : an ancient family of receptors signaling infection
Imler JL & Hoffmann JA
Abstract : Innate immunity is the first-line host defense of multicellular organisms that rapidly operates to limit infection upon exposure to microbes. It involves intracellular signaling pathways in the fruit-fly Drosophila and in mammals that show striking similarities. Recent genetic and biochemical data have revealed, in particular, that proteins of the Toll family play a critical role in the immediate response to infection. We review here the recent developments on the structural and functional characterization of this evolutionary ancient and important family of proteins, which can function as cytokine receptors (Toll in Drosophila) or pattern recognition receptors (TLR4 in mammals) and activate similar, albeit non identical signal transduction pathways, in flies and mammals.
| Reviews in Immunogenetics
2000: Vol 2, 294-304 | Abstract
Article complet | A microfluometer assay to measure the expression of b-galactosidase and GFP reporter genes in single Drosophila flies
Jung AC, Criqui MC, Rutschmann S, Hoffmann JA & Ferrandon D
Abstract : beta-galactosidase and green fluorescent protein (GFP) are among the most commonly used reporter genes to monitor gene expression in various organisms including Drosophila melanogaster. Their expression is usually detected in a qualitative way by direct microscopic observations of cells, tissues, or whole animals. To measure in vivo the inducibility of two antimicrobial peptide genes expressed during the Drosophila innate immune response, we have adapted two reporter gene systems based on the beta-galactosidase enzymatic activity and GFP. We have designed a 96-well microplate fluorometric assay sensitive enough to quantify the expression of both reporter genes in single flies. The assay has enabled us to process efficiently and rapidly a large number of individual mutant flies generated during an ethylmethane sulfonate saturation mutagenesis of the Drosophila genome. This method may be used in any screen that requires the quantification of reporter gene activity in individual insects.
| Biotechniques
2000: Vol 30, 594-601. | Abstract
Article complet | Mosquito-Plasmodium interactions in response to immune activation of the vector
Lowenberger CA, Kamal S, Chiles J, Paskewitz S, Bulet P, Hoffmann JA & Christensen BM
Abstract : During the development of Plasmodium sp. within the mosquito midgut, the parasite undergoes a series of developmental changes. The elongated ookinete migrates through the layers of the midgut where it forms the oocyst under the basal lamina. We demonstrate here that if Aedes aegypti or Anopheles gambiae, normally susceptible to Plasmodium gallinaceum and P. berghei, respectively, are immune activated by the injection of bacteria into the hemocoel, and subsequently are fed on an infectious bloodmeal, there is a significant reduction in the prevalence and mean intensity of infection of oocysts on the midgut. Only those mosquitoes immune activated prior to, or immediately after, parasite ingestion exhibit this reduction in parasite development. Mosquitoes immune activated 2-5 days after bloodfeeding show no differences in parasite burdens compared with naive controls. Northern analyses reveal that transcriptional activity for mosquito defensins is not detected in the whole bodies of Ae. aegypti from 4 h to 10 days after ingesting P. gallinaceum, suggesting that parasite ingestion, passage from the food bolus through the midgut, oocyst formation, and subsequent release of sporozoites into the hemolymph do not induce the production of defensin. However, reverse transcriptase-PCR of RNA isolated solely from the midguts of Ae. aegypti indicates that transcription of mosquito defensins occurs in the midguts of naive mosquitoes and those ingesting an infectious or noninfectious bloodmeal. Bacteria-challenged Ae. aegypti showed high levels of mature defensin in the hemolymph that correlate with a lower prevalence and mean intensity of infection with oocysts. Because few oocysts were found on the midgut of immune-activated mosquitoes, the data suggest that some factor, induced by bacterial challenge, kills the parasite at a preoocyst stage.
| Exp. Parasitol.
1999: 91, 59-69 | Abstract
Article complet | A GFP-drosomycin reporter transgene reveals a local immune response in Drosophila that is not dependent on the Toll pathway
Ferrandon D, Jung AC, Criqui MC, Lemaitre B, Uttenweiler-Joseph S, Michaut L, Reichhart JM & Hoffmann JA
Abstract : A hallmark of the systemic antimicrobial response of Drosophila is the synthesis by the fat body of several antimicrobial peptides which are released into the hemolymph in response to a septic injury. One of these peptides, drosomycin, is active primarily against fungi. Using a drosomycin-green fluorescent protein (GFP) reporter gene, we now show that in addition to the fat body, a variety of epithelial tissues that are in direct contact with the external environment, including those of the respiratory, digestive and reproductive tracts, can express the antifungal peptide, suggesting a local response to infections affecting these barrier tissues. As is the case for vertebrate epithelia, insect epithelia appear to be more than passive physical barriers and are likely to constitute an active component of innate immunity. We also show that, in contrast to the systemic antifungal response, this local immune response is independent of the Toll pathway.
| EMBO J
1998: 17, 1217-1227 | Abstract
Article complet | Phylogenetic perspectives in innate immunity
Hoffmann JA, Kafatos FC, Janeway CA Jr & Ezekowitz RAB
Abstract : The concept of innate immunity refers to the first-line host defense that serves to limit infection in the early hours after exposure to microorganisms. Recent data have highlighted similarities between pathogen recognition, signaling pathways, and effector mechanisms of innate immunity in Drosophila and mammals, pointing to a common ancestry of these defenses. In addition to its role in the early phase of defense, innate immunity in mammals appears to play a key role in stimulating the subsequent, clonal response of adaptive immunity.
| Science
1999: 284, 1313-1318 | Abstract
Article complet | A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins Dorsal and DIF
Manfruelli P, Reichhart JM, Steward R, Hoffmann JA & Lemaitre B
Abstract : Expression of the gene encoding the antifungal peptide Drosomycin in Drosophila adults is controlled by the Toll signaling pathway. The Rel proteins Dorsal and DIF (Dorsal-related immunity factor) are possible candidates for the transactivating protein in the Toll pathway that directly regulates the drosomycin gene. We have examined the requirement of Dorsal and DIF for drosomycin expression in larval fat body cells, the predominant immune-responsive tissue, using the yeast site-specific flp/FRT recombination system to generate cell clones homozygous for a deficiency uncovering both the dorsal and the dif genes. Here we show that in the absence of both genes, the immune-inducibility of drosomycin is lost but can be rescued by overexpression of either dorsal or dif under the control of a heat-shock promoter. This result suggests a functional redundancy between both Rel proteins in the control of drosomycin gene expression in the larvae of Drosophila. Interestingly, the gene encoding the antibacterial peptide Diptericin remains fully inducible in the absence of the dorsal and dif genes. Finally, we have used fat body cell clones homozygous for various mutations to show that a linear activation cascade Spaetzle--> Toll-->Cactus-->Dorsal/DIF leads to the induction of the drosomycin gene in larval fat body cells.
| EMBO J.
1999: 18, 3380-3391 | Abstract
Article complet | Constitutive activation of Toll-mediated antifungal defense in serpin-deficient Drosophila
Levashina E, Langley E, Green C, Gubb D, Ashburner M, Hoffmann JA & Reichhart JM
Abstract : The antifungal defense of Drosophila is controlled by the spaetzle/Toll/cactus gene cassette. Here, a loss-of-function mutation in the gene encoding a blood serine protease inhibitor, Spn43Ac, was shown to lead to constitutive expression of the antifungal peptide drosomycin, and this effect was mediated by the spaetzle and Toll gene products. Spaetzle was cleaved by proteolytic enzymes to its active ligand form shortly after immune challenge, and cleaved Spaetzle was constitutively present in Spn43Ac-deficient flies. Hence, Spn43Ac negatively regulates the Toll signaling pathway, and Toll does not function as a pattern recognition receptor in the Drosophila host defense.
| Science
1999: 285 1917-1919 | Abstract
Article complet | A novel insect defensin from the ant Formica rufa
Taguchi S, Bulet P, Hoffmann JA
Abstract : By combination of size exclusion and reversed-phase chromatography, we have isolated a novel member of insect defensin-type antimicrobial peptides from the entire bodies of bacteria-challenged Formica rufa (hymenoptera, formicidae). The molecular mass of the purified peptide was estimated to be 4120.42 by matrix-assisted laser desorption/ionization-time of flight/mass spectrometry. Sequence analysis revealed that this peptide consisted of 40 amino acid residues with six cysteines engaged in the formation of three intramolecular disulfide bridges. This peptide is unique among the arthropod defensins in terms of the presence of asparatic acid and alanine at position 33 and as C-terminal residue, respectively. In addition, this novel defensin from Formica rufa has the particularity to have no C-terminal extension in contrast to those reported for other hymenoptera defensins.
| Biochimie
1998: 80 (4), 343-6 | Abstract
Article complet | Antimicrobial peptides from insects, In Molecular Mechanisms of Immune Responses in Insects
Hetru C, Hoffmann D & Bulet P
Abstract :
| Eds Brey PT & Hultmark D, Chapman & Hall
1998: pp 40-66 | Abstract
Article complet | In vivo regulation of the IkB homologue cactus during the immune response of Drosophila
Nicolas E, Reichhart JM, Hoffmann JA & Lemaitre B
Abstract : The dorsoventral regulatory gene pathway (spatzle/Toll/cactus) controls the expression of several antimicrobial genes during the immune response of Drosophila. This regulatory cascade shows striking similarities with the cytokine-induced activation cascade of NF-kappaB during the inflammatory response in mammals. Here, we have studied the regulation of the IkappaB homologue Cactus in the fat body during the immune response. We observe that the cactus gene is up-regulated in response to immune challenge. Interestingly, the expression of the cactus gene is controlled by the spatzle/Toll/cactus gene pathway, indicating that the cactus gene is autoregulated. We also show that two Cactus isoforms are expressed in the cytoplasm of fat body cells and that they are rapidly degraded and resynthesized after immune challenge. This degradation is also dependent on the Toll signaling pathway. Altogether, our results underline the striking similarities between the regulation of IkappaB and cactus during the immune response.
| J. Biol. Chem
1998: 273, 10463-10469 | Abstract
Article complet | Plasmodium gallinaceum : differential killing of some mosquito stages of the parasite by insect defensin
Shahabuddin M, Fields I, Bulet P, Hoffmann JA & Miller LH
Abstract : We examined several insect antimicrobial peptides to study their effect on Plasmodium gallinaceum zygotes, ookinetes, oocysts, and sporozoites. Only two insect defensins-Aeschna cyanea (dragon fly) and Phormia terranovae (flesh fly)-had a profound toxic effect on the oocysts in Aedes aegypti and on isolated sporozoites. The defensins affected the oocysts in a time-dependent manner. Injecting the peptide into the hemolymph 1 or 2 days after an infectious blood meal had no significant effect on prevalence of infection or relative oocyst density per mosquito. When injected 3 days after parasite ingestion, the relative oocyst density was significantly reduced. Injection on day 4 or later damaged the developing oocysts, although the oocysts density per mosquito was not significantly different when examined on day 8. The oocysts were swollen or had extensive internal vacuolization. The peptides had no detectable effect on the early stages of the parasite: the zygotes and ookinetes tested in vitro. Both the defensins were highly toxic to isolated sporozoites in vitro as indicated by disruption of the membrane permeability barrier, a change in morphology, and loss of motility. In contrast to the toxicity of cecropin and magainin for mosquitoes, defensin, at concentrations that kill parasites, is not toxic to mosquitoes, suggesting that defensin should be studied further as a potential molecule to block sporogonic development of Plasmodium.
| Exp. parasitol
1998: 89, 103-112 | Abstract
Article complet | Differential display of peptides during the immune response of Drosophila : a matrix-assisted laser desorption ionization time-of-flight mass spectrometry study
Uttenweiler-Joseph S, Moniatte M, Van Dorsselaer A, Hoffmann JA & Bulet P
Abstract : We have developed an approach based on a differential mass spectrometric analysis to detect molecules induced during the immune response of Drosophila, regardless of their biological activities. For this, we have applied directly matrix-assisted laser desorption/ionization MS to hemolymph samples from individual flies before and after an immune challenge. This method provided precise information on the molecular masses of immune-induced molecules and allowed the detection, in the molecular range of 1.5-11 kDa, of 24 Drosophila immune-induced molecules (DIMs). These molecules are all peptides, and four correspond to already characterized antimicrobial peptides. We have further analyzed the induction of the various peptides by immune challenge in wild-type flies and in mutants with a compromised antimicrobial response. We also describe a methodology combining matrix-assisted laser desorption ionization time-of-flight MS, HPLC, and Edman degradation, which yielded the peptide sequence of three of the DIMs. Finally, molecular cloning and Northern blot analyses revealed that one of the DIMs is produced as a prepropeptide and is inducible on a bacterial challenge.
| Proc. Natl. Acad Sci. USA
1998: 95, 11342-11347 | Abstract
Article complet | Analysis of the Drosophila host defense in domino mutant larvae, which are devoid of hemocytes
Braun A, Hoffmann JA & Meister M
Abstract : We have analyzed the Drosophila immune response in domino mutant larvae, which are devoid of blood cells. The domino mutants have a good larval viability, but they die as prepupae. We show that, on immune challenge, induction of the genes encoding antimicrobial peptides in the fat body is not affected significantly in the mutant larvae, indicating that hemocytes are not essential in this process. The hemocoele of domino larvae contains numerous live microorganisms, the presence of which induces a weak antimicrobial response in the fat body. A full response is observed only after septic injury. We propose that the fat body cells are activated both by the presence of microorganisms and by injury and that injury potentiates the effect of microorganisms. Survival experiments after an immune challenge showed that domino mutants devoid of blood cells maintain a wild-type resistance to septic injury. This resistance was also observed in mutant larvae in which the synthesis of antibacterial peptides is impaired (immune deficiency larvae) and in mutants that are deficient for humoral melanization (Black cells larvae). However, if domino was combined with either the immune deficiency or the Black cell mutation, the resistance to septic injury was reduced severely. These results establish the relevance of the three immune reactions: phagocytosis, synthesis of antibacterial peptides, and melanization. By working in synergy, they provide Drosophila a highly effective defense against injury and/or infection.
| Proc. Natl. Acad. Sci. USA
1998: 95, 14337-14342 | Abstract
Article complet | Cysteine-rich antimicrobial peptides in invertebrates
Dimarcq JL, Bulet P, Hetru C & Hoffmann JA
Abstract : Antimicrobial peptides are pivotal elements of the innate immune defense against bacterial and fungal infections. Within the impressive list of antimicrobial peptides available at present, more than half have been characterized in arthropods. Cysteine-rich antimicrobial peptides represent the most diverse and widely distributed family among arthropods and, to a larger extent, among invertebrates. Proeminent groups of cysteine-rich peptides are peptides with the CS alpha beta motif and peptides forming an hairpin-like beta-sheet structure. Although these substances exhibit a large structural diversity and a wide spectrum of activity, they have in common the ability to permeabilize microbial cytoplasmic membranes. Drosophila has proved a remarkable system for the analysis of the regulation of expression of gene encoding antimicrobial cysteine-rich peptides. These studies have unraveled the striking parallels that exist between insect immunity and innate immunity in mammals that point to a common ancestry of essential aspects of innate immunity.
| Biopolymers (Peptide Science)
1998: 47, 465-477 | Abstract
Article complet | Drosophila immunity.
HOFFMANN JA, REICHHART JM
Abstract :
| Trends in Cell Biology
1997 : 7 309-316 | Abstract
Article complet | Solution structure of drosomycin, the first inducible antifungal protein from insects.
LANDON C, SODANO P, HETRU C, HOFFMANN JA, PTAK M
Abstract :
| Protein Science
1997 : 6 1878-1884 | Abstract
Article complet | Drosophila host defense : differential induction of antimicrobial peptide genes after infection by various classes of microorganisms.
LEMAITRE B, REICHHART JM, HOFFMANN JA
Abstract :
| Proc. Natl. Acad. Sci. USA
1997 : 94 14614-14619 | Abstract
Article complet | Treatment of l(2)mbn Drosophila tumorous blood cells with the steroid hormone ecdysone amplifies the inducibitity of antimicrobial peptide gene expression.
DIMARCQ JL, IMLER JL, LANOT R, EZEKOWITZ A, HOFFMANN JA, JANEWAY C & LAGUEUX M (1997).
Abstract :
| Insect Biochem. & Molec. Biol.
1997 : 27 877-886 | Abstract
Article complet | Drosophila immunity : a comparative analysis of the Rel proteins dorsal and Dif in the induction of the genes encoding diptericin and cecropin.
GROSS I, GEORGEL P, KAPPLER C, REICHHART JM, HOFFMANN JA
Abstract :
| Nucleic Acids Res.
1996 : 24 1238-1245 | Abstract
Article complet | Innate immunity in insects.
HOFFMANN JA, REICHHART JM, HETRU C
Abstract :
| Current Opinion in Immunology
1996 : 8 8-13 | Abstract
Article complet | Inducible immune factors of the vector mosquito Anopheles gambiae : biochemical purification of a defensin antibacterial peptide and molecular cloning of preprodefensin cDNA.
RICHMAN A, BULET P, HETRU C, BARILLAS-MURY C, HOFFMANN JA, KAFATOS F
Abstract :
| Insect Molec. Biol.
1996 : 5 203-210 | Abstract
Article complet | Innate immunity. Isolation of several cystein-rich antimicrobial peptides from the blood of a mollusc, Mytillus edulis.
CHARLET M, CHERNYSH S, PHILIPPE H, HETRU C, HOFFMANN JA, BULET P
Abstract :
| J. Biol. Chem.
1996 : 271 21808-21813 | Abstract
Article complet | The dorsoventral regulatory gene cassette spaetzle/toll/cactus controls the potent antifungal response in Drosophila adults.
LEMAITRE B, NICOLAS E, MICHAUT L, REICHHART JM, HOFFMANN JA
Abstract :
| Cell
1996 : 86 973-983 | Abstract
Article complet | Functional analysis and regulation of nuclear import of dorsal during the immune response in Drosophila.
LEMAITRE B, MEISTER M, GOVIND S, GEORGEL P, STEWARD R, REICHHART, HOFFMANN JA
Abstract :
| EMBO J.
1995 : 14 536-545 | Abstract
Article complet | Drosophila immunity. A sequence homologous to mammalian interferon consensus response elements enhances the activity of the diptericin promoter.
GEORGEL P, KAPPLER C, LANGLEY E, GROSS I, NICOLAS E, REICHHART JM, HOFFMANN JA
Abstract :
| Nucleic Acids Res.
1995 : 23 1140-1145 | Abstract
Article complet | Refined three-dimensional solution structure of insect defensin A.
CORNET B, BONMATIN JM, HETRU C, HOFFMANN JA, PTAK M, VOVELLE F
Abstract :
| Structure
1995 : 3 435-448 | Abstract
Article complet | Insect immunity. The inducible antibacterial peptide diptericin carries two O-glycans necessary for biological activity.
BULET P, HEGY G, LAMBERT J, VAN DORSSELAER A, HOFFMANN JA, HETRU C
Abstract :
| Biochemistry
1995 : 34 7394-7400 | Abstract
Article complet | A recessive mutation, immune-deficiency (imd), defines two distinct control pathways in the Drosophila host defense.
LEMAITRE B, KROMER-METZGER E, MICHAUT L, NICOLAS E, MEISTER M, GEORGEL P, REICHHART JM, HOFFMANN JA
Abstract :
| Proc. Natl. Acad. Sci. USA
1995 : 92 9465-9469 | Abstract
Article complet | Metchnikowin, a novel immune-inducible proline-rich peptide from Drosophila with antibacterial and antifungal properties.
LEVASHINA E, OHRESSER S, BULET P, REICHHART JM, HETRU C, HOFFMANN JA
Abstract :
| Eur. J. Biochem.
1995 : 233 694-700 | Abstract
Article complet | Insect Immunity : Isolation of three novel inducible antibacterial defensins from the vector mosquito, Aedes aegypti.
LOWENBERGER C, BULET P, CHARLET M, HETRU C, HODGEMAN B, CHRISTENSEN B, HOFFMANN JA
Abstract :
| Insect Biochem. Molec. Biol.
1995 : 25 867-873 | Abstract
Article complet | Structure-activity analysis of thanatin, a novel 21-residue inducible insect defense peptide with sequence homology to frog skin antimicrobial peptides.
FEHLBAUM P, BULET P, CHERNYSH S, BRIAND JP, ROUSSEL JP, LETELLIER L, HETRU C, HOFFMANN JA
Abstract :
| Proc. Natl. Acad. Sci. USA
1995 : 93 1221-1225 | Abstract
Article complet | Insect immunity. A transgenis analysis in Drosophila defines several functional domains in the diptericin promoter
Meister M, Braun A, Kappler C, Reichhart JM and Hoffmann JA.
Abstract :
| EMBO J.
1994: 13, 5958-5966. | Abstract
Article complet | Characterization and transcriptional profiles of a Drosophila gene encoding an insect defensin. A study in insect immunity.
DIMARCQ JL, HOFFMANN D, MEISTER M, BULET P, LANOT R, REICHHART JM, HOFFMANN JA
Abstract :
| Eur. J. Biochem.
1994 : 221 201-209 | Abstract
Article complet | The inducible antibacterial peptides of insects.
COCIANCICH S, BULET P, HETRU C, HOFFMANN JA
Abstract :
| Parasitology Today
1994 : 10 n° 4 132-139 | Abstract
Article complet | Novel inducible antibacterial peptides from a Hemipteran insect, the sap-sucking bug Pyrrhocoris apterus.
COCIANCICH S, DUPONT A, HEGY G, LANOT R, HOLDER F, HETRU C, HOFFMANN JA, BULET P
Abstract :
| Biochem. J.
1994 : 300 567-575 | Abstract
Article complet | Antibacterial peptides/polypeptides in the insect host defense. A comparison with vertebrate antibacterial peptides/polypeptides.
HETRU C, BULET P, COCIANCICH S, DIMARCQ JL, HOFFMANN D, HOFFMANN JA
Abstract :
| Ed. by Hoffmann JA, Janeway Ch, Natori S.R.G. Landes Company.
1994, Austin, Georgetown | Abstract
Article complet | Immune Gene expression in Drosophila. In "Phylogenetic Perspectives in Immunity".
MEISTER M, GEORGEL P, LEMAITRE B, KAPPLER C, LAGUEUX M, REICHHART JM, HOFFMANN JA
Abstract :
| Ed. by Hoffmann JA, Janeway Ch, Natori S.R.G. Landes Company
1994, Austin, Georgetown | Abstract
Article complet | Septic injury of Drosophila induces the synthesis of a potent antifungal peptide with sequence homology to plant antifungal peptides.
FEHLBAUM P, BULET P, MICHAUT L, LAGUEUX M, BROEKAERT W, HETRU C, HOFFMANN JA
Abstract :
| J. Biol. Chem.
1994 : 269 33159-33163 | Abstract
Article complet | A novel inducible antibacterial peptide of Drosophila carries an O-glycosylated substitution.
BULET P, DIMARCQ JL, HETRU C, LAGUEUX M, CHARLES M, HEGY G, VAN DORSSELAER A, HOFFMANN JA
Abstract :
| J. Biol. Chem.
1993 : 268 14893-14897 | Abstract
Article complet | The humoral antibacterial response of Drosophila.
HOFFMANN JA, HETRU C, REICHHART JM
Abstract :
| FEBS Lett.
1993 : 325, 63-66 | Abstract
Article complet | Insect defensin, an inducible antibacterial peptide, forms voltage-dependent channels in Micrococcus luteus.
COCIANCICH S, GHAZI A, HETRU C, HOFFMANN JA, LETELLIER L
Abstract :
| J. Biol. Chem.
1993 : 268, 19239-19245 | Abstract
Article complet | Expression and nuclear translocation of the rel/NF-kB-related morphogen dorsal during the immune response of Drosophila.
REICHHART JM, GEORGEL P, MEISTER M, LEMAITRE B, KAPPLER C, HOFFMANN JA
Abstract :
| C.R. Acad. Sci.
1993 : Paris 316, 1218-1224. | Abstract
Article complet | Insect Immunity : the diptericin promoter contains multiple functional regulatory sequences homologous to mammalian acute-phase response elements.
GEORGEL P, MEISTER M, KAPPLER C, LEMAITRE B, REICHHART JM, HOFFMANN JA
Abstract :
| BBRC
1993 : 197 508-517 | Abstract
Article complet | Insect Immunity. Developmental and inducible activity of the Drosophila diptericin promoter.
REICHHART JM, MEISTER M, DIMARCQ JL, ZACHARY D, HOFFMANN D, RUIZ C, RICHARDS G, HOFFMANN JA
Abstract :
| EMBO J.
1992 : 11 n° 4 1469-1477 | Abstract
Article complet | Expression and secretion in yeast of active insect defensin, an inducible antibacterial peptide from the fleshfly Phormia terranovae.
REICHHART JM, PETIT I, LEGRAIN M, DIMARCQ JL, KEPPI E, LECOCQ JP, HOFFMANN JA, ACHSTETTER T
Abstract :
| Inv. Reprod. Develop.
1992 : 21 n° 1 15-24 | Abstract
Article complet | A novel insect defensin mediates the inducible antibacterial activity in larvae of the dragonfly Aeschna cyanea (Paleoptera, Odonata).
BULET P, COCIANCICH S, REULAND M, SAUBER F, BISCHOFF R, HEGY G, VAN DORSSELAER A, HETRU C, HOFFMANN JA
Abstract :
| Eur. J. Biochem.
1992 : 209 977-984 | Abstract
Article complet | Insect defensins, inducible antibacterial peptides of the insect host defence.
HOFFMANN JA, HETRU C
Abstract :
| Immunol. Today
1992 : 13 n° 10 411-415 | Abstract
Article complet | Insect Immunity. Two 17-bp repeats nesting a kB-related sequence confer inducibility to the diptericin gene and bind a polypeptide in bacteria-challenged Drosophila.
KAPPLER C, MEISTER M, LAGUEUX M, GATEFF E, HOFFMANN JA, REICHHART JM
Abstract :
| EMBO J.
1993 : 12 n° 4 1561-1568 | Abstract
Article complet | Synthesis of a tritiated 3-dehydroecdysteroid putative precursor of ecdysteroid biosynthesis in Locusta migratoria.
DOLLE F, HETRU C, ROUSSEL JP, ROUSSEAU B, SOBRIO F, LUU B, HOFFMANN JA
Abstract :
| Tetrahedron
1991 : 47 7067-7080 | Abstract
Article complet | Isolation and structural characterization of an insulin-related molecule, a predominant neuropeptide from Locusta migratoria (Insecta, Orthoptera)
HETRU C, LI KW, BULET P, LAGUEUX M, HOFFMANN JA
Abstract :
| Eur. J. Biochem.
1991 : 201 495-499 | Abstract
Article complet | Determination of disulfide bridges in natural and recombinant insect defensin A.
LEPAGE P, BITSCH F, ROECKLIN D, KEPPI E, DIMARCQ JL, REICHHART JM, HOFFMANN JA, ROITSCH C, VAN DORSSELAER A
Abstract :
| Eur. J. Biochem.
1991 : 196 735-742 | Abstract
Article complet | Insect Immunity. Isolation from a coleopteran insect of a novel inducible antibacterial peptide and of new members of the insect defensin family.
BULET P, COCIANCICH S, DIMARCQ JL, LAMBERT J, REICHHART JM, HOFFMANN D, HETRU C, HOFFMANN JA
Abstract :
| J. Biol. Chem.
1991 : 266 n° 36 24520-24525 | Abstract
Article complet | Two-dimensional 1H-NMR study of recombinant insect defensin A in water. Resonance assignments, secondary structure and global folding.
BONMATIN JM, BONNAT JL, GALLET X, VOVELLE F, REICHHART JM, HOFFMANN JA, PTAK M
Abstract :
| J. Biol. NMR
1991 : 2 235-256 | Abstract
Article complet | Insect Immunity. Expression of the two major inducible antibacterial peptides, defensin and diptericin, in Phormia terranovae.
DIMARCQ JL, ZACHARY D, HOFFMANN JA, HOFFMANN D, REICHHART JM
Abstract :
| EMBO J. 9
1990 : n° 8, 2507-2515 | Abstract
Article complet | Synthesis of high specific activity [3H2-1,2]-7-dehydrocholesterol. Conversion to ecdysone in follicle cells of Locusta (Insects).
DOLLE F, KAPPLER C, HETRU C, ROUSSEAU B, COPPO M, LUU B, HOFFMANN JA
Abstract :
| Tetrahedron 46
1990 : n°15 5305-5316 | Abstract
Article complet | Insect Immunity. Characterization of a Drosophila cDNA encoding a novel member of the diptericin family of immune peptides and expression studies.
WICKER C, REICHHART JM, HOFFMANN D, HULTMARK D, SAMAKOVLIS C, HOFFMANN JA
Abstract :
| J. Biol. Chem.
1990 : 265 n° 36 22493-22498 | Abstract
Article complet | Insect immunity. Isolation from immune blood of the Dipteran Phormia terranovae of two novel antibacterial peptides with sequence homology to rabbit lung macrophage bactericidal peptides
LAMBERT J, KEPPI E, DIMARCQ JL, WICKER, C, REICHHART JM, DUNBAR B, LEPAGE P, VAN DORSSELAER A, HOFFMANN JA, FOTHERGILL J, HOFFMANN D
Abstract :
| Proc. Nat. Acad. Sci.
1989 : USA 86 262-266 | Abstract
Article complet | Enzymes involved in the biosynthesis of ecdysone. In "Ecdysone"
KAPPLER C, HETRU C, DURST F, HOFFMANN JA
Abstract :
| J. Koolman Ed. Thieme Verlag-Berlin.
1989, pp 161-166 | Abstract
Article complet | Allenic cholesteryl derivatives as inhibitors of ecdysone biosynthesis
BURGER A, ROUSSEL JP, HETRU C, HOFFMANN JA, B. LUU B
Abstract :
| Tetrahedron
1989 : 45 155-164 | Abstract
Article complet | Insect Immunity. Isolation of cDNA clones corresponding to diptericin, an inducible antibacterial peptide from Phormia terranovae (Diptera). Transcriptional profiles during immunization
REICHHART JM, ESSRICH M, DIMARCQ JL, HOFFMANN D, HOFFMANN JA, LAGUEUX M
Abstract :
| Eur. J. Biochem.
1989 : 182 423-427 | Abstract
Article complet | L-Canavanine incorporation into vitellogenin and macromolecular conformation.
ROSENTHAL GA, REICHHART JM, HOFFMANN JA
Abstract :
| J. Biol. Chem.
1989 : 264, 13693-13696 | Abstract
Article complet | Characterization of three hydroxylases involded in the final steps of biosynthesis of the steroid hormone ecdysone in Locusta migratoria (Insecta, Orthoptera)
Kappler C, Kabbouh M, Hetru C, Durst F and Hoffmann JA
Abstract :
| J. Steroid Biochem.
1988 : 31, 891-898. | Abstract
Article complet | Insect immunity. Characterization of a family of novel inducible antibacterial proteins from immunized larvae of the dipteran Phormia terranovae and complete amino acid sequence of the predominant member, diptericin A
DIMARCQ JL, KEPPI E, DUNBAR B, LAMBERT J, REICHHART JM, HOFFMANN D, RANKINE SM, FOTHERGILL JE, HOFFMANN JA
Abstract :
| Europ. J. Biochem.
1988 : 171 17-22 | Abstract
Article complet | Study of the biosynthesis of ecdysone. Part IV. Synthesis of high specific activity (3H2-22,23)-2,22-dideoxyecdysone. Tissue distribution of the C-22 hydroxylase in Locusta migratoria
HAAG T, HETRU C, KAPPLER C, MOUSTIER AM, HOFFMANN JA. LUU B
Abstract :
| Tetrahedron
1988 : 44 1397-1408 | Abstract
Article complet | In vitro studies on potential selective and irreversible inhibitors of enzymes involved in the biosynthesis of ecdysone
BURGER A, ROUSSEL JP, COLOBERT F, KAPPLER C, HETRU C, LUU B, HOFFMANN JA
Abstract :
| J. of Pesticide Biochem. and Physiol.
1987 : 29 197-208 | Abstract
Article complet | Studies on the C-2 hydroxylation of 2-deoxyecdysone in Locusta migratoria
KAPPLER C, KABBOUH M, DURST F, HOFFMANN JA
Abstract :
| Insect Biochem.
1986 : 16 25-32 | Abstract
Article complet | Role of the follicle cells and the oocytes in ecdysone biosynthesis and esterification in vitellogenic females of Locusta migratoria.
KAPPLER C, GOLTZENÉ F, LAGUEUX M, HETRU C, HOFFMANN JA
Abstract :
| Int. J. Invert. Reprod. Develop.
1986 : 9 17-34 | Abstract
Article complet | Role of ecdysteroids in reproduction of Insects : a critical analysis. In "Advances in Invertebrate Reproduction"
HOFFMANN JA, LAGUEUX M, HETRU C, KAPPLER C, GOLTZENÉ F, LANOT R, THIEBOLD J
Abstract :
| M. Porchet, J.C. Andries and A. Dhainaut-Eds. Elsevier, Amsterdam, New York.
1986, Oxford, pp 9-22 | Abstract
Article complet | Ecdysone conjugates : isolation and identification. In "Methods in Enzymology".
HETRU C, LUU B, HOFFMANN JA
Abstract :
| J.H. Law and H.C. Rilling Eds. Academic Press Orlando 111.
1985, part B 411-419 | Abstract
Article complet | Recherches sur la conversion in vitro d'un précurseur de biosynthèse d'ecdysone, la 2,22,25-tridésoxyecdysone, par des tissus embryonnaires et larvaires de Locusta migratoria (Insecte Orthoptère)
MEISTER M, DIMARCQ JL, KAPPLER C, LAGUEUX M, HETRU C, LUU B, HOFFMANN JA
Abstract :
|
1985 : Paris 300 347-352 | Abstract
Article complet | Conversion of radiolabelled ecdysone precursor, 2,22,25-tridésoxyecdysone, by embryonic and larval tissues of Locusta migratoria
MEISTER M, DIMARCQ JL, KAPPLER C, HETRU C, LAGUEUX M, LANOT R, LUU B, HOFFMANN JA
Abstract :
| Molec. Cell. Endocrinol.
1985 : 41 27-44 | Abstract
Article complet | Steroid hormones in Invertebrates.
HOFFMANN JA, HETRU C, LAGUEUX M, CHARLET M, HIRN M
Abstract :
| Nova Acta Leopoldina Leipzig
1984 : 255 56-317 | Abstract
Article complet | Ecdysteroids in ovaries and embryos of Locusta migratoria. Biosynthesis metabolism and mode of action of invertebrate hormones
LAGUEUX M, HOFFMANN JA, GOLTZENÉ F, KAPPLER C, TSOUPRAS G, HETRU C, LUU B.
Abstract :
| J.A. Hoffmann and M. Porchet Eds.
Springer Verlag-Heidelberg, 1984, pp 168-180 | Abstract
Article complet | Cycle de mue et ecdystéroïdes chez une sangsue, Hirudo medicinalis.
SAUBER F, REULAND M, BERCHTOLD JP, HETRU C, TSOUPRAS G, LUU B, MORITZ ME, HOFFMANN JA
Abstract :
| C. R. Acad. Sci.
1983 : Paris 296 413-418 | Abstract
Article complet | Conversion in vitro de 20-hydroxyecdysone en métabolites phosphorylés et acétylés par des complexes tube digestif-tubes de Malpighi de larves de Locusta migratoria
TSOUPRAS G, LUU B, HETRU C, MULLER JF, HOFFMANN JA
Abstract :
| C. R. Acad. Sci.
1983 : Paris 296 77-80 | Abstract
Article complet | Identification and metabolic fate of ovarian 22-adenosine-monophosphoric ester of 2-deoxyecdysone in ovaries and eggs of an insect, Locusta migratoria.
TSOUPRAS G, HETRU C, LUU B, CONSTANTIN E, LAGUEUX M, HOFFMANN JA
Abstract :
| Tetrahedron Letters
1983 : 39 1789-1796 | Abstract
Article complet | Synthesis of high specific activity (23,24)3H4-2-deoxyecdysone
HETRU C, NAKATANI Y, LUU B, HOFFMANN JA
Abstract :
| Nouveau J. de Chimie
1983 : 27 587-591 | Abstract
Article complet | Ecdysone. Endocrinology of Insects.
HOFFMANN JA, HETRU C.
Abstract :
| R.G.H. Downer and H. Laufer
Eds. Alan R. Liss New York, 1983: pp 65-88 | Abstract
Article complet | Fate of maternal conjugated ecdysteroids during embryonic development in Locusta migratoria
SALL C, TSOUPRAS G, KAPPLER C, LAGUEUX M, ZACHARY D, LUU B, HOFFMANN JA
Abstract :
| J. Insect Physiol.
1983 : 29 491-507 | Abstract
Article complet | The biosynthetic pathway of ecdysone : studies with vitellogenic ovaries of Locusta migratoria (Orthoptera)
HETRU C, KAPPLER C, HOFFMANN JA, NEARN R, LUU B, HORN DHS
Abstract :
| Molec. Cell. Endocrinol.
1982 : 26 51-80 | Abstract
Article complet | The major conjugates of ecdysteroids in young eggs and in embryos of Locusta migratoria
TSOUPRAS G, HETRU C, LUU B, LAGUEUX M, CONSTANTIN E, HOFFMANN JA
Abstract :
| Tetrahedron Letters
1982 : 23 2045-2048 | Abstract
Article complet | Ecdysteroids and ovarian development in the shore crab, Carcinus maenas.
LACHAISE, F, GOUDEAU M, HETRU C, KAPPLER C, HOFFMANN JA
Abstract :
| Hoppe-Seyler's Z. Physiol. Chem.
1981 : 362 521-529 | Abstract
Article complet | Ecdysone in reproductively competent female adults and in embryos of insects. In "Progress in Ecdysone Research".
HOFFMANN JA, LAGUEUX M, HETRU C, CHARLET M, GOLTZENE F
Abstract :
| Hoffmann JA Ed. Elsevier, North-Holland.
1980, pp 431-465 | Abstract
Article complet | Prothoracic gland activity and blood titres of ecdysone and ecdysterone during the last larval instar of Locusta migratoria
HIRN M, LAGUEUX M, HETRU C, HOFFMANN JA
Abstract :
| J. Insect Physiol.
1979: 25 255-261 | Abstract
Article complet | Ecdysone titre and metabolism in correlation to cuticulogenesis during embryonic development in Locusta migratoria
LAGUEUX M, HETRU C, GOLTZENE F, KAPPLER C, HOFFMANN JA
Abstract :
| J. Insect Physiol.
1979: 25 709-723 | Abstract
Article complet | Adult ovaries of Locusta migratoria contain the sequence of biosynthetic intermediate for ecdysone
LAGUEUX M, HETRU C, LUU B, HOFFMANN JA
Abstract :
| Life Sciences
1978: 22 2141-2154 | Abstract
Article complet |
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