Trends in Immunology
Regulators of the Toll and Imd pathways in the Drosophila innate immune response
Section snippets
Signal-dependent regulation of the Drosophila antimicrobial response
On infection, insects mount a rapid antimicrobial response that consists of many components, such as antimicrobial peptides, complement-like proteins and blood cells 1, 2, 3, 4, 5, 6. Insects do not have counterparts of mammalian B and T lymphocytes, and therefore the insect antimicrobial response does not exhibit a high degree of antigen-targeting specificity. Nonetheless, insects can recognize different classes of microorganisms and respond differentially 7, 8, 9, 10. Moreover, the components
Pattern recognition in the Toll pathway
Toll is a transmembrane receptor first identified as an essential component in dorsal–ventral embryonic development in Drosophila [15]. Although many of the Toll pathway components were characterized based on their embryonic phenotypes, recent genetic studies using immune deficiency phenotypes (i.e. reduced survival of animals after septic injury or reduced immunity gene expression) have provided further insights into this pathway 16, 17, 18. Stimulation of the Toll pathway by Gram-positive
Novel insights into the mechanism of Toll signaling
Toll activation involves receptor multimerization. Using various chimeric and mutant constructs, it has been demonstrated that multimerization of Toll increases signaling activity 25, 26. Moreover, in vitro experiments have shown that a dimer of truncated Spätzle can link with two molecules of the Toll ectodomain, suggesting that an in vivo function of Spätzle is to induce the dimerization of Toll [24]. The contention of Toll and TLR multimerization fits well with published results 27, 28.
Pattern recognition in the Imd pathway
Imd is an adaptor protein homologous to the TNFR-interacting protein receptor interacting protein (RIP) [51]. The Imd pathway governs the expression of many antimicrobial peptide genes in response to Gram-negative bacterial infection 1, 2, 3, 4. The pattern-recognition receptor for the Imd pathway appears to be PGRP-LC, which contains a putative transmembrane domain 32, 33 (Figure 4). The loss-of-function mutants of another PGRP, the PGRP-LE, also cause reduced expression of antimicrobial
The Imd pathway has multiple branches
Many signaling components downstream of Imd have been identified by forward and reverse genetics 1, 2, 3, 4 (Figure 4). So far, TAK1 (transforming growth factor-β-activated kinase 1) is the most upstream kinase of the cascade. TAK1 activates the Drosophila IKK complex that contains at least the IKKβ and IKKγ homologues, which are encoded by the ird5 and kenny genes, respectively 18, 39, 40, 41, 42. The Drosophila IKK complex directs the site-specific proteolytic cleavage and activation of
Summary
The most significant findings in Drosophila innate immunity in the last few years are the identification of many upstream recognition molecules for various microorganisms and microbial compounds. The PGRP family of pattern-recognition receptors greatly expands our knowledge of the insect innate immune response and provides an interesting comparison to the Toll and TLR family. The Drosophila Toll and Imd pathways have been relatively well characterized, however, further understanding of these
Acknowledgements
The work in our laboratory is support by an NIH grant (GM53269).
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