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Chapter 1 : Invertebrate Innate Immune Defenses
Category: Immunology; Clinical Microbiology
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All metazoans are able to mount an innate immune response. Whereas invertebrate species rely solely on this type of defense, gnathostome vertebrates have developed, in addition, a sophisticated adaptive immune system centered on lymphocytes that are absent from invertebrates. Importantly, these adaptive responses require strong stimulatory signals from cells of the innate immune system, and during infections in vertebrates, both arms of defenses cross talk in their fight against invading microorganisms. This chapter reviews the currently available data from the simplest metazoan species, the Porifera and Cnidaria, in an attempt to trace the origin of essential elements of the innate immune system. The Drosophila host defense comprises both humoral and cellular reactions. The hallmark of the humoral response is the challenge-induced synthesis, mainly by the fat-body cells, of potent antimicrobial peptides (AMPs) and their secretion into the hemolymph (blood). The best characterized member in Drosophila is eater, a type I transmembrane receptor with 32 typical EGF-like repeats in its extracellular domain. Biochemical assays have allowed the in vitro reconstruction of the proteolytic cascade activated downstream of TmGNBP3, TmPGRP-SA, and TmGNBP1. This work led to the identification of the apical protease, DmModSP, acting downstream of PRRs for the activation of the Toll pathway in Drosophila. Investigations of the immune reactions of several Annelid and Mollusk species have revealed a potent cellular arm of defense, involving phagocytosis, encapsulation, and production of lytic activities often referred to as natural killer-like (NK) activities.
Peptidoglycans as inducers of the Drosophila Toll and IMD signaling pathways. Peptidoglycan (PGN) is a glucopeptide polymer consisting of long chains of alternating N-acetylglucosamine and N-acetylmuramic acid residues connected to each other by short peptide bridges. The nature of the peptide bridge varies depending on the bacterial strains. Most gram-positive bacterial PGN carries a lysine residue at the third amino acid position in the peptide stems (Lys-type PGN), that is replaced by a diaminopimelic acid residue in most gram-negative bacteria (DAP-type PGN). In Drosophila, sensing of Lys-type PGN and DAP-type PGN is mediated by dedicated recognition PGRPs that activate the Toll and IMD pathways, respectively. Catalytic PGRPs have a zinc-dependant amidase activity (scissors). They reduce the immune stimulatory potency of PGN by removing the peptide bridges from the sugar backbone.
Activation of the Drosophila Toll pathway during fungal and gram-positive bacterial infections. The Toll receptor is activated by a proteolytically processed form of the cytokine-like polypeptide spaetzle (present as a dimer in the hemolymph). Microbial cell wall components (right panel) interact with circulating receptors (fungal β-glucans with GNBP3; gram-positive bacterial peptidoglycan (PGN) with a PGRP-SA/GNBP1 complex). This recognition activates, via a still unidentified mechanism, a proteolytic cascade including the zymogen modular serine protease (ModSP) and the serine protease grass, leading to the activation of the spaetzle processing enzyme (SPE), which cleaves pro-spaetzle into its active Toll-ligand form. Alternatively, microbial secreted proteases (left panel) can activate the circulating zymogen persephone, which, directly or indirectly (still unknown), activates SPE to cleave pro-spaetzle.
Characteristic structural domains of Drosophila Toll and Toll9 and of mammalian TLR2.
The Antiviral Response in Drosophila. RNA interference and inducible gene reprograming are two major arms of the Drosophila antiviral defense. Viral nucleic acids are recognized by the RNase III enzyme dicer 2, which activates the small interfering RNA (siRNA) pathway leading to the degradation of viral RNA. In addition, dicer 2 can trigger the inducible expression of a variety of genes via a yet unidentified signaling pathway. Among the induced genes is that encoding the vago cystein-rich polypeptide, which is involved in the control of the viral load. Further, a cytokine-mediated response activated upon viral infection leads to the expression of genes via the activation of the JAK/STAT pathway in neighboring cells. The mechanism controlling this antiviral-inducible response is so far unknown.