WNV infection of primary embryonic fibroblasts recovered from RIG-I 2/2 mice revealed that RIG-I was important in eliciting innate antiviral immune defenses early during infection, whereas MDA5 was important for enhancing and sustaining this response [21] . We further evaluated WNV infection of RIG-I 2/2 or MDA5 2/2 mice and confirmed that RIG-I serves a dominant role among the RLRs for the acute induction of innate immune defenses and protection against WNV infection in vivo (data not shown). Since the RLRs signal innate defenses through the IPS-1 adaptor protein [29] , we also examined the role of IPS-1 in protection against WNV infection upon a sub-lethal virus challenge of wild type and IPS-1 2/2 mice. IPS-1 2/2 mice were highly susceptible to WNV infection and exhibited 100% mortality with an average survival time (AST) of 7.3 days as compared to wild type mice (38.5% mortality with an AST of 13.2 days; p,0.0001; Fig 1A) . Thus, RIG-I and IPS-1-dependent signaling are essential for protection against WNV infection.