The RLRs, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation antigen 5 (MDA5) [13, 14, 15, 16] , are PRRs that play critical roles in triggering immune defenses against RNA virus infection, including WNV. RIG-I and MDA5 are cytosolic RNA helicases that contain an amino terminal tandem caspase activation and recruitment domain (CARD). Upon engaging RNA substrates, the RLRs undergo a conformational change and bind to the mitochondrial associated protein, interferon promoter stimulator-1 (IPS-1) through a CARD-CARD interaction, leading to IPS-1-dependent signaling of IFN production and expression of immune response genes [17, 18] . RLR signaling and IPS-1 function have an essential role in triggering IFN defenses during WNV infection of mouse embryo fibroblasts (MEFs) and human cell lines in vitro. Cells lacking either RIG-I or MDA5 were attenuated in their ability to generate an effective innate immune response to infection, whereas cells lacking both RIG-I and MDA5 or those deficient in IPS-1 alone were unable to respond to infection with WNV and related flaviviruses [19, 20, 21, 22] . Recent studies examined the role of another class of pattern recognition receptors, Toll like receptor (TLR)3 and TLR7, and show that these receptors are also important PRRs of WNV infection, as they play a role in signaling IFN production and an inflammatory response upon viral ligand recognition [23, 24, 25] . TLR3 has been shown to contribute to both enhancement and protection of CNS inflammation and neurovirulence of WNV in vivo [23, 24] , while TLR7-dependent signaling was shown to be essential for directing proper immune cell homing to sites of WNV infection during the adaptive immune response in vivo [25] .