Induction of an innate immune response following infection can occur as a result of the activation of pattern recognition receptors (PRRs), commonly known as Toll-like receptors (TLRs). TLRs recognize many elements of foreign pathogens, including LPS, flagellin, and dsRNA, and initiate signaling cascades that result in the production of type I interferons. Accumulating data suggests that genetic variation in TLRs and their associated signaling components modulates the response to TLR ligands and, consequently, the inflammatory immune response [67] . TLR3 is constitutively expressed on lung alveolar and bronchial epithelial cells and has been shown to contribute to the secretion of multiple cytokines following influenza A infection [68] . Given the data suggesting that H5N1 pathogenicity is due in part to alterations in innate immune responses and hypercytokinemia, it is plausible that polymorphisms altering TLR function could contribute to susceptibility or protection from infection. This hypothesis is supported by a genetic study of a case of influenza-associated encephalopathy, a condition associated with apoptosis and hypercytokinemia [45] . In this case, a missense mutation (908T/C) in the TLR3 gene was identified and was shown to be a loss-of-function mutation, suggesting a protective role for TLR3 signaling in severe influenza infection [45] ( Table 2) . Although these results are consistent with studies suggesting a protective effect of TLR3 in West Nile infection [69] , they are at odds with TLR3 null mouse studies, which have shown reduced proinflammatory cytokine production following cellular stimulation [70] [71] [72] . Consequently, the contribution of TLR genetic variants to H5N1 inflammatory responses remains to be resolved.