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The Host Defense of Drosophila Melanogaster

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The Host Defense of Drosophila Melanogaster ANRV306-IY25-24 ARI 11 February 2007 13:14 The Host Defense of Drosophila melanogaster Bruno Lemaitre1 and Jules Hoffmann2 1Centre de Gen´ etique´ Moleculaire,´ CNRS, 91198 Gif-sur-Yvette, France; email: [email protected] 2Institut de Biologie Moleculaire´ et Cellulaire, UPR 9022 du CNRS, 67084 Strasbourg Cedex, France; email: [email protected] Annu. Rev. Immunol. 2007. 25:697–743 Key Words First published online as a Review in Advance on insect immunity, Toll, Imd, recognition, pathogens January 2, 2007 The Annual Review of Immunology is online at Abstract immunol.annualreviews.org To combat infection, the fruit fly Drosophila melanogaster relies on by Swiss Academic Library Consortia on 01/22/09. For personal use only. This article’s doi: multiple innate defense reactions, many of which are shared with 10.1146/annurev.immunol.25.022106.141615 higher organisms. These reactions include the use of physical bar- Annu. Rev. Immunol. 2007.25:697-743. Downloaded from arjournals.annualreviews.org Copyright c 2007 by Annual Reviews. riers together with local and systemic immune responses. First, ep- All rights reserved ithelia, such as those beneath the cuticle, in the alimentary tract, and 0732-0582/07/0423-0697$20.00 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, pro- duces humoral response molecules including antimicrobial peptides. Here we review our current knowledge of the molecular mecha- nisms underlying Drosophila defense reactions together with strate- gies evolved by pathogens to evade them. 697 ANRV306-IY25-24 ARI 11 February 2007 13:14 INTRODUCTION receptor of the Drosophila Tollsignaling path- way, also regulate innate immune responses Insects and microorganisms coexist within the in mammals. The conservation of a signal- AMP: antimicrobial biosphere in numerous ways. Frequently, in- ing pathway for the activation of antimicrobial peptide sect larvae develop in decaying organic mat- defense responses suggests that some compo- RNAi: RNA ter, and insect adults often serve as vectors nents of innate immunity share an ancient ori- interference for microorganisms causing plant and ani- gin in metazoan evolution and demonstrates mal diseases. Thus insects have evolved sensi- that is a potent model for deci- tive mechanisms for recognition of pathogens Drosophila phering general innate immune mechanisms and an array of strategies to defend them- in animals. Investigations on the highly effi- selves against attacks by bacteria, fungi, par- cient immune reactions in this Dipteran in- asites, and viruses. To combat infection, the sect have also provided information on other fruit fly Drosophila melanogaster relies on mul- insects that have dramatic repercussions on tiple innate defense reactions that are par- human life as agricultural pests or as vectors tially shared with higher organisms (1–4) for diseases such as malaria (e.g., the mosquito (Figure 1). The mechanisms regulating these ). immune responses have been largely uncov- Anopheles The completion of the ge- ered with the aid of genetic and molecular Drosophila nomic sequence in 2000 (6) and the subse- studies in Drosophila. The key role of the quent expansion of new postgenomic tech- Drosophila model for studying immunity was nologies including proteomics, microarrays, illustrated by the initial genetic identification and RNAi (RNA interference) have consid- of signaling pathways mediating antimicrobial erably widened the possibilities of immune peptide (AMP) gene expression (5). Relatives system analysis in this model organism. This of the Toll receptor protein, the cell surface Cytokines (Upd-3) Lymph glands Circulating PRRs Serine proteases/ GNBPs/PGRPs serpins PGRP-LC Toll Domeless Toll Imd JAK/ STAT pathway pathway pathway by Swiss Academic Library Consortia on 01/22/09. For personal use only. Annu. Rev. Immunol. 2007.25:697-743. Downloaded from arjournals.annualreviews.org Lamellocyte Plasmatocyte Crystal cell Fat body Antimicrobial peptides, Encapsulation Phagocytosis Coagulation Melanization iron sequestration, DIMs, serine proteases/serpins, stress factors (turandots), opsonization (TEPs), clotting factors (fondue) HEMOLYMPH Figure 1 Schematic overview of Drosophila host defense. Detection of microbial pathogens elicits a large array of interconnected and synergistic defense modules in immune-responsive tissues. 698 Lemaitre · Hoffmann ANRV306-IY25-24 ARI 11 February 2007 13:14 article presents an overview of our current AMP production by the fat body, which is knowledge of the Drosophila immune response a major immune-responsive tissue that origi- in the context of two fundamental ques- nates from the mesoderm during embryoge- ROS: reactive tions: (a) What are the molecular mechanisms nesis and acquires its immune competence at oxygen species underlying the defense reactions? (b) How the onset of the first larval stage. Due to its does each of these mechanistic modules con- large size and its location inside the open cir- tribute to defense during an infection, and culatory system of the insect body cavity, the what strategies have been developed by the fat body represents a powerful organ for the pathogens to evade them? synthesis and secretion of peptides into the hemolymph, where they readily reach their effective concentrations. REPERTOIRE OF DROSOPHILA DEFENSE MECHANISMS Immune effectors. Among the various A hallmark of the Drosophila host defense, and molecules produced by the fat body in re- that of most other holometabolous insects, sponse to infection, AMPs are the best char- is the challenge-induced synthesis and secre- acterized. Some 20 immune-inducible AMPs, tion of potent AMPs that accumulate in the which can be grouped into seven classes, hemolymph where they oppose invading mi- have been identified (Figure 2). They are croorganisms. Although synthesis of AMPs small (<10 kDa), with the exception of the is probably common to all metazoans, secre- 25 kDa Attacin, and cationic and exhibit tion of these molecules into the hemolymph a broad range of activities against bacte- is not a general phenomenon. We refer it to ria and/or fungi (8). Diptericin, Drosocin, as the “systemic immune response,” which is and Attacin are very effective against Gram- by far the best analyzed among Drosophila im- negative bacteria (9–11). Defensin is active mune reactions, and analyze it from the syn- against Gram-positive germs (12), whereas thesis of immune effectors to recognition of Drosomycin and Metchnikowin are antifun- infection. Epithelial immunity, i.e., the fight gal agents (13, 14). Cecropin A1 acts against against invading microorganisms at the level both bacteria and some fungi (15, 16). De- of the barrier epithelia, is now understood fensins and Cecropins have been reported to significantly contribute to the protection from many insects, whereas Drosomycin and of Drosophila. This response is analyzed next Metchnikowin have so far been identified both in terms of AMP and reactive oxygen only in Drosophilidae (8). The insect AMPs species (ROS) production. A subsequent sec- are membrane-active, and their precise mode tion deals with the cellular response by the of action at the membrane level is still un- by Swiss Academic Library Consortia on 01/22/09. For personal use only. hemocytes, especially their role in phagocy- der investigation. Some AMPs are very sta- tosis and encapsulation of parasites. The final ble owing to the presence of intramolecu- Annu. Rev. Immunol. 2007.25:697-743. Downloaded from arjournals.annualreviews.org section is devoted to two reactions, coagula- lar disulfide bridges and are still detected in tion and melanization, which are activated im- the hemolymph several weeks after challenge mediately upon injury. (17). Experiments with transgenic flies over- expressing a single AMP provided support for a critical role of AMPs in resistance to infec- The Systemic Immune Response tion in Drosophila (18). However, the particu- Injection of bacteria into the body cavity in- lar contributions of each of these AMPs have duces the appearance of antimicrobial activity not been tested, as loss-of-function mutants in the hemolymph of Drosophila. This activity for AMP genes are not available to date. persists for several days and can confer protec- Recent large-scale analyses, at the tran- tion against a second challenge by pathogenic scriptome and proteome levels, have re- bacteria (7). This reaction mainly consists of vealed that in addition to that of AMPs, the www.annualreviews.org • Host Defense of Drosophila melanogaster 699 ANRV306-IY25-24 ARI 11 February 2007 13:14 by Swiss Academic Library Consortia on 01/22/09. For personal use only. Annu. Rev. Immunol. 2007.25:697-743. Downloaded from arjournals.annualreviews.org Figure 2 Drosophila antimicrobial peptides. Name, number of genes in the genome, antimicrobial activities, estimated concentration in the hemolymph after bacterial injection, and 3-D structure (8) (nd, not determined). production of many peptides and proteins is systemic immune response itself (e.g., signal- upregulated after septic injury (19–25).1 Some ing components). Another group of proteins of these are involved in the regulation of the (opsonins, components of the melanization or clotting system) participates in distinct de- fense
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