The essential, non-redundant roles of RIG-I and MDA5 in detecting and controlling West Nile virus infection (P1385)

Abstract Virus recognition by the innate immune system represents a critical component of host defense against infection. Proper activation of innate immunity and full immune protection to the emerging infectious disease of West Nile virus has previously been shown to be dependent on viral recognition by the host RIG-I-like receptor (RLR) protein family. RIG-I and MDA5 are the two members of the RLR family that have been shown to recognize viral RNA and to activate innate immune programs that suppress infection. In the current study we have expanded our understanding of the role of the RLRs in protection against West Nile virus infection by assessing the individual roles of RIG-I and MDA5 both in vitro and in vivo. The loss of either gene alone results in a deficit of innate immune signaling and virus control in vitro and increased mortality in vivo. Loss of both RIG-I and MDA5 results in a near complete absence of innate immune gene induction in key target cells of infection and a more severe pathogenesis very similar to that of cells and animals lacking the RLR central signaling adaptor MAVS. Additionally, we have shown that cells infected with West Nile virus contain two distinct pathogen associated molecular patterns that are sensed by RIG-I and MDA5 respectively. Our results highlight the necessity of multiple pattern recognition receptors in the same pathway acting in concert to affect a successful immunological outcome.