Key Points
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A defining feature of insect innate immunity is the existence of an efficient systemic humoral immune response that fights off microbial infections alongside cellular immune responses. This response relies on the inducible synthesis and release of potent antimicrobial peptides in the body cavity (haemocoele).
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Two distinct pathways control the expression of genes that encode antibacterial and/or antifungal peptides. The Toll pathway is required for the resistance against fungi and some Gram-positive bacteria, whereas the immune deficiency (IMD) pathway mediates resistance against most Gram-negative bacterial strains.
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Activation of the Toll or IMD pathways by bacteria relies on the detection of their peptidoglycan by pattern-recognition receptors (PRRs) belonging to the peptidoglycan-recognition protein (PGRP) family. PGRPs discriminate between lysine-type and diaminopimelic acid (DAP)-type peptidoglycans, and activate accordingly either the Toll or the IMD pathway.
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A second family of PRRs (known as Gram-negative binding proteins (GNBPs) or β-glucan recognition proteins (βGRPs)) is involved in the detection of bacterial and fungal infections for Toll pathway activation. GNBP1 is required together with PGRPs for sensing some Gram-positive bacterial strains, whereas GNBP3 detects fungal β-(1,3)-glucans.
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The detection of microbial infection in flies does not solely rely on PRRs. A fungal virulence factor, the PR1 protease, triggers Toll pathway activation in parallel to PRRs.
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The Toll and IMD signalling pathways activate distinct members of the nuclear factor-κB (NF-κB) family in flies. These pathways are evolutionary ancient and evoke respectively the Toll-like receptor (TLR)/interleukin-1 receptor and the tumour-necrosis factor (TNF) signalling pathways that have a pivotal role in mammalian innate immunity.
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-κB (NF-κB) 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.
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Acknowledgements
We thank Drs Chang, Deisenhofer, Ho, Lim and Troxler for input on Figure 2.
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Supplementary information
Supplementary information S1 (table)
Properties of antimicrobial peptides (PDF 168 kb)
Supplementary information S2 (figure)
Microbial inducers of the Drosophila melanogaster systemic immune response. (PDF 235 kb)
Supplementary information S3 (figure)
Mammalian Toll–like receptor 9 (TLR9)signalling pathway. (PDF 202 kb)
Supplementary information S4 (figure)
TNF and TLR4 signalling in mammals. (PDF 267 kb)
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Glossary
- Haemolymph
-
Insects have an open circulatory system. The haemolymph is the blood-like fluid that bathes tissues and is circulated throughout the body cavity by the dorsal vessel, a functional equivalent of the heart.
- Melanization
-
The deposition of melanin at the site of injury as a result of the activation of a biochemical cascade involving a key enzyme, phenol oxidase, which is activated in response to septic injury. This activation releases toxic reactive oxygen species that may attack invading microbes. Although this mechanism is highly conserved in invertebrates, a primary role of melanization in host defence remains to be firmly established.
- Peptidoglycan-recognition proteins
-
(PGRPs). This family is characterized by the presence of one or several PGRP domains that present similarities to bacteriophage amidases. This family has been conserved throughout evolution. Catalytic and non-catalytic PGRPs are also found in vertebrates in which they act as amidases or antimicrobial peptides.
- Malpighian tubules
-
The excretory and osmoregulatory organs of insects that open near the junction of the midgut and hindgut.
- Gram-negative binding proteins
-
(GNBPs; also known as βGRPs). This family is characterized by the existence of an N-terminal glucan-binding domain and a C-terminal domain with similarities to bacterial glucanases. GNBPs are present in most invertebrates, including deuterostomes, such as the sea urchin Strongylocentrotus purpuratus, but has not been found in vertebrates.
- Pattern-recognition receptor
-
A germ-line encoded receptor that recognizes unique and essential structures that are present in microorganisms, but absent from the host. In vertebrates, signalling through these receptors leads to the production of pro-inflammatory cytokines and chemokines and to the expression of co-stimulatory molecules by antigen-presenting cells. The expression of co-stimulatory molecules, together with the presentation of antigenic peptides, by antigen-presenting cells couples innate immune recognition of pathogens with the activation of adaptive immune responses.
- Zymogen
-
The inactive precursor of a protease. The zymogen contains an amino-terminal pro-domain that keeps the protease in an inactive state. The removal of the pro-domain by another protease or by autoproteolysis leads to a conformational change that exposes the active site.
- CLIP domain
-
CLIP domains are disulphide-knotted protein–protein interaction domains that are present in several invertebrate serine proteases and mediate sequential activation of immune zymogen cascades.The topology of the knot formed by the disulphide bonds is reminiscent of that of a paper clip, hence its name.
- Polyubiquitylation
-
The attachment of the small protein ubiquitin to lysine residues present in other proteins. Protein ubiquitylation occurs in three enzymatic steps requiring a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). Subsequent ubiquitylation events can extend from the initial ubiquitin at one of its seven lysine residues (K6, K11, K27, K29, K33, K48 or K63) forming a polyubiquitin chain.
- Receptor-interacting protein
-
(RIP). A family of serine/threonine kinases with homologous kinase domains. RIP1 is recruited to TNFR1 and mediates TNF-induced activation of JNK and NF-κB transcriptional pathways. RIP2 (CARDIAK/RICK) binds to caspase-1 and activates NF-κB.
- RHIM motif
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In mammals, the RHIM motif is found in the adaptor proteins TIR-domain-containing adaptor protein inducing IFNβ (TRIF), which is part of the TLR pathway, and RIP, which is part of both the TLR and TNFR pathways. This motif is required for the interaction between RIP and TRIF and subsequent NF-κB activation by TLR3.
- K63-linked ubiquitylation
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Formation of polyubiquitin chains on a target protein that are linked through the lysine at position 63 (K63) in ubiquitin. Unlike K48-linked chains, which are the principal signal for targeting substrates for proteasomal degradation, K63-linked ubiquitin-modified proteins regulate protein function, target certain proteins for endocytosis, and interact with proteins with specific ubiquitin-binding domains.
- S2 cells
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A cell-line established by Imogen Schneider (S2 stands for Schneider's line 2) in 1970, from Drosophila embryos. S2 cells are the most widely used Drosophila cell line. Of particular interest for the study of innate immunity, these cells share several properties with haemocytes, in particular the Toll- and IMD-mediated induction of AMPs, and have the capacity to phagocytose microorganisms.
- Redox homeostasis
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The protection that is conferred to the fly against the toxic oxidative response that is triggered in the gut in response to the ingestion of high doses of microbes. This protection is mediated by immune regulated catalase (IRC), the transcription of which is also triggered in response to septic injury.
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Ferrandon, D., Imler, JL., Hetru, C. et al. The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections. Nat Rev Immunol 7, 862–874 (2007). https://doi.org/10.1038/nri2194
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DOI: https://doi.org/10.1038/nri2194
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