RIG-I-Like Receptors control unique innate immune responses following West Nile Virus infection

Abstract

Abstract RIG-I-like Receptors (RLRs), RIG-I, MDA5 and LGP2, play critical roles in innate immune defense against RNA viruses and are central to host immunity. RIG-I and MDA5 signal through CARDs to induce innate immune activation while LGP2 lacks these signaling domains but is thought to function as an RLR cofactor. During West Nile Virus (WNV) infection RIG-I and MDA5 work in tandem to initiate innate immune responses but the role of LGP2 in WNV innate immunity is not well-defined. Here we applied virologic, genetic, and bioinformatics approaches to assess innate immune signaling and global gene expression response to WNV infection in primary mouse embryonic fibroblasts (MEFs) and bone marrow derived macrophages (BMMs) from mice lacking RIG-I, MDA5, or LGP2, as well as from mice lacking both RIG-I and MDA5 (DKO). RNAseq analysis defined the distinct roles of RIG-I and MDA5 in induction of innate immune gene expression against WNV. Importantly, we found that LGP2 uniquely controls genes involved in innate immunity when compared to RIG-I and MDA5. We identify an LGP2-specific gene signature that reveals a unique, non-redundant role in innate immunity against WNV. Further, we used a multiplex cytokine assay to determine unique cytokine profiles for each RLR-deficient cell type, suggesting that these distinct transcriptomes lead to functional consequences in response to WNV. A model of unique actions of RLRs in WNV infection will be presented.