Conclusions

Rapid progress has been made over the past decade in the identification and functional characterization of receptors responsible for induction and maintenance of antimicrobial and antiviral innate immune responses. TLRs have been shown to represent principal sensors of bacterial and viral infections, as well as receptors involved in recognition of "danger" endogenous proteins, oligosaccharides, and nucleic acids released as a consequence of cellular damage. The extreme complexity and potential for cross-talk within the MyD88-dependent and MyD88-independent TLR signaling pathways has been revealed, and several TLR polymorphisms have been associated with predisposition to a number of infectious diseases or reducing the risk for development of inflammatory diseases, e.g., atherosclerosis. Because of the central role for IRAK-4 in TLR signaling, it is perhaps no surprise that mutations within the kinase domain of IRAK-4 have been shown to severely affect antibacterial immune defense mechanisms. This defect is associated with the failure of mutant IRAK-4 species to form functional signaling complexes with receptor and intracellular components of the IL-1R/TLR4 pathway. The capacity of overexpressed, truncated IRAK-4 species to inhibit assembly of signaling complexes among wild-type IRAK-1, TLR4, and MyD88 may be employed for possible future therapeutic intervention in hyperinflammatory states by using kinase-inactive IRAK-4 mimetics to inhibit signaling. Future studies will likely reveal the feasibility of such an approach, and delineate how mutations within TLRs and IRAK-4 affect other antibacterial immune defense mechanisms, including the development of adaptive immunity.

Acknowledgements This work was supported by NIH grants AI47233, AI057490, AI44936, AI18797 (to S.N.V.), and AI-059524 (to A.E.M.).

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