The Toll Pathway

The production of AMPs by insect haemocytes and the fat body is an essential part of the insect immune response (Khush et al., 2001; Silverman & Maniatis, 2001). The production of these AMP has largely been attributed to the activation of a NF-K-like transcription factor (Engstrom, 1999). The Toll (Figure 3.3) and IMD pathways in insects activate two distinct NF-K-like transcription factors. The Toll pathway was first discovered in Drosophila (Lemaitre et al., 1996; Horng & Medzhitov, 2001; Tauszig-Delamasure et al., 2002) and later a number of TLRs were identified in vertebrates. The Toll pathway is similar to the TLR/interleukin-1 receptor (IL-1R) pathway involved in the innate immune response of vertebrates (Khush et al., 2001; Silverman & Maniatis, 2001). Toll is a transmembrane protein receptor with an extracellular leucin-rich repeat (LRR) domain and an intracellular domain similar to that of the IL-1R in vertebrates. This domain is referred to as the Toll/IL-1R (TIR) domain. The Toll receptor is not considered a PRR, as it does not directly recognise antimicrobial surfaces, rather a series of proteolytic reactions initiated by the presence of invading microbes results in the generation of the active form of the Spatzle protein, which is the ligand for the Toll receptor (Lemaitre et al., 1996; Ferrandon et al., 2004). Toll activation is triggered by Gram-positive or fungal infections and is initiated by the dimerisation of the Toll molecules (Weber et al., 2003). This dimerisation is thought to induce the recruitment of het-ero-trimeric complexes composed of Myd88, Pelle, and Tube. The Myd88 protein and Pelle are homologues of the human Myd88 and IL-1-receptor-associated kinases (IRAK), respectively. The Myd88 protein contains a death domain (DD) and a TIR domain, the later of which interacts with Toll through its TIR domain. Tube and Pelle also contain DDs required for interaction of Tube with Myd88 and Pelle, but Myd88 and Pelle to not directly interact (Sun et al., 2002). Formation of

Figure 3.3 Diagrammatic representation of the similarities between the invertebrate and vertebrate Toll cascades. The activation of transcription factors NF-kP in vertebrates and the NF-kP-like factor, Dif, in Drosophila is initiated by the activation of homologous Toll receptors. This initiates a cascade of reactions ultimately resulting in the breakdown of parallel inhibitory proteins I-kP in vertebrates and Cactus in Drosophila. TLR pathway in vertebrates activates the production of pro-inflammatory cytokines such as IL-1, IL-6, and IL-8

Figure 3.3 Diagrammatic representation of the similarities between the invertebrate and vertebrate Toll cascades. The activation of transcription factors NF-kP in vertebrates and the NF-kP-like factor, Dif, in Drosophila is initiated by the activation of homologous Toll receptors. This initiates a cascade of reactions ultimately resulting in the breakdown of parallel inhibitory proteins I-kP in vertebrates and Cactus in Drosophila. TLR pathway in vertebrates activates the production of pro-inflammatory cytokines such as IL-1, IL-6, and IL-8

the hetero-trimeric adaptor complex results in the activation of the Pelle kinase and the subsequent hydrolysis of the cactus inhibitor. Cactus is homologous to the NF-k inhibitor of vertebrates, namely I-kP (Geisler et al., 1992), and functions in a similar manner by inhibiting the activity of the dorsal-related immune factor (DIF), a homologue of vertebrate NF-k (Ip et al., 1993). Hydrolysis of cactus results in the release of DIF, which enters the nucleus and activates the expression of many

AMPs including the antifungal defensin drosomycin (Nicolas et al., 1998; Tauszig-Delamasure et al., 2002; Belvin et al., 1996). The kinase activity of Pelle is required for cactus degradation (Towb et al., 2001) and cactus must be phosphorylated in order to be degraded (Fernandez et al., 2001), however, Pelle has not been shown to directly phosphorylate cactus and another unknown kinase may be involved. Considering published data, the Drosophila Toll family consists of eight members; among them are the 18-wheeler receptor, the Toll receptor, and Toll-3 to Toll-8 (Imler & Hoffmann, 2000).

The Toll pathways activation is also involved in other aspects of the insect immune response, other than AMP production. The Toll pathway activates NF-k which is required for the elimination of the Serpin27A serine protease inhibitor required to keep ProPO in its inactive form (Petros et al., 2002). This indicates crosstalk between the Toll pathway and the phenoloxidase cascade in insects.

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