| P&barbelow;attern R&barbelow;ecognition R&barbelow;eceptors (PRRs) are conserved, germ-line-encoded receptors of the innate immune system that recognize invariant, P&barbelow;athogen A&barbelow;ssociated M&barbelow;olecular P&barbelow;atterns (PAMPs) produced by microbial organisms. The best-characterized PRRs are a class of receptors called T&barbelow;oll-L&barbelow;ike R&barbelow;eceptors (TLRs) found in invertebrate and vertebrate animals. Upon recognizing PAMPs, mammalian TLRs activate intracellular signaling pathways essential for the generation of effective innate and adaptive immune responses. Targets of TLR signaling pathways include MAP kinases and the transcription factor NF-κB; induction of inflammatory cytokines; and upregulation of the costimulatory molecules required for the activation of naïve T lymphocytes. In addition to these core responses, recent studies have shown that members of the TLR family can elaborate distinct host defense responses, implying an additional level of specificity and diversity in TLR signaling. I have identified a novel adapter protein, TIRAP (TIR-domain containing A&barbelow;dapter P&barbelow;rotein), and characterized its function through in vitro studies. I have also generated TIRAP-deficient mice and used them to investigate the function of TIRAP in innate host defense pathways induced by TLRs. These studies have shown that TIRAP is the first signaling protein utilized exclusively by TLRs, and is critical for signal transduction by a subset of TLRs. TIRAP is thus the first adapter protein known to be differentially involved in TLR signaling and is one of the means by which individual TLRs can induce distinct innate immune responses to microbial infection.; In Drosophila, the induction of antimicrobial peptides by Toll is required for defense against fungal and gram-positive pathogens. I have identified a novel adapter in the Toll signaling pathway, dMyD88. I have shown that dMyD88 can interact with Toll and downstream components of the Toll pathway, and induce the promoter of Toll-dependent antimicrobial peptides. dMyD88 is therefore a critical component of a host defense pathway in flies. In addition, dMyD88 can interact with two novel Drosophila proteins, dFADD and Dredd, which are implicated in apoptosis. Interestingly, the dMyD88-dFADD-Dredd pathway is similar in design to the TNFR pathway in mammals, which may suggest that it is the evolutionary ancestor of mammalian death receptor pathways. |
