Melanoma Differentiation-Associated Gene 5 (MDA5) Is Involved in the Innate Immune Response to Paramyxoviridae Infection In Vivo

Abstract

The early host response to pathogens is mediated by several distinct pattern recognition receptors. Cytoplasmic RNA helicases including RIG-I and MDA5 have been shown to respond to viral RNA by inducing interferon (IFN) production. Previous in vitro studies have demonstrated a direct role for MDA5 in the response to members of the Picornaviridae, Flaviviridae and Caliciviridae virus families ((+) ssRNA viruses) but not to Paramyxoviridae or Orthomyxoviridae ((−) ssRNA viruses). Contrary to these findings, we now show that MDA5 responds critically to infections caused by Paramyxoviridae in vivo. Using an established model of natural Sendai virus (SeV) infection, we demonstrate that MDA5^−/− mice exhibit increased morbidity and mortality as well as severe histopathological changes in the lower airways in response to SeV. Moreover, analysis of viral propagation in the lungs of MDA5^−/− mice reveals enhanced replication and a distinct distribution involving the interstitium. Though the levels of antiviral cytokines were comparable early during SeV infection, type I, II, and III IFN mRNA expression profiles were significantly decreased in MDA5^−/− mice by day 5 post infection. Taken together, these findings indicate that MDA5 is indispensable for sustained expression of IFN in response to paramyxovirus infection and provide the first evidence of MDA5-dependent containment of in vivo infections caused by (−) sense RNA viruses. The innate immune system possesses an array of sensory molecules which are purposed in detecting viral nucleic acids. Our understanding of how these molecular sensors detect viral nucleic acids continues to evolve. Herein, we demonstrate that MDA5, a member of the RIG-I-like receptor family, is involved in the detection of paramyxovirus infection in vivo. Specifically, MDA5 appears to trigger antiviral cytokines that inhibit paramyxovirus replication. In this regard, mice that are deficient in MDA5 are unable to express sustained levels of these cytokines and thus succumb to extensive viral propagation and disease. Our findings are largely discordant from previous in vitro studies using cultured cells, where it has been shown that RIG-I and not MDA5 is involved in the innate response to negative sense RNA viruses. Thus, our data provides strong evidence of MDA5-based detection of negative sense RNA viruses, and furthermore underscore the importance of organism-based analysis of the innate system.