Conclusions

Extreme complexity and a potential for cross-talk within the TLR signaling pathways suggest that mutations in almost any receptors or intracellular signaling components would result in severe innate immune deficiency. However, to date, relatively few mutations have been described that underlie deficient TLR4 signaling and increased susceptibility to infectious disease. These include mutations in TLR4, the IRAK-4 enzyme, and in NEMO (IKKy) and iKBa components of the IKK signaling complex. Due to the central role for IRAK-4 in mediating TLR-mediated signal transduction, IRAK-4 mutations severely affect antibacterial immune defense mechanisms. This defect is associated with mutations within the kinase domain of IRAK-4 that seem to inhibit the formation of functional signaling complexes with receptor and intracellular components of the IL-1R/TLR4 pathway. This property of truncated IRAK-4 molecules also raises the possibility for therapeutic intervention in hyperinflammatory states by using IRAK-4 mimetics to inhibit signaling. Future studies will likely reveal the feasibility of such an approach, and delineate how IRAK-4 deficiency affects other antibacterial immune defense mechanisms, including development of adaptive immunity.

Acknowledgements

This work was supported by NIH grants AI-059524 (AEM) AI-18797, AI-44936, and AI-57575 (SNV), and with federal funds from the NCI, NIH, under Contract No. N01-C0-I2400 (DBK and JIG).

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