Role of enteroviral RNA-dependent RNA polymerase in regulation of MDA5-mediated interferon-β activation

Abstract

Infection of enteroviruses can cause severe neurological complications in humans. The interactions between the enteroviral and host proteins may facilitate the virus replication and be involved in pathogenicity of infected individuals. It has been shown that human enteroviruses possess various mechanisms to suppress host innate immune responses in infected cells. Previous studies showed that infection of enterovirus 71 could cause degradation of MDA5, which is a critical cytoplasmic pathogen sensor in recognition of picornaviruses for initiating transcription of type I interferon. In the present study, we demonstrated that the RNA-dependent RNA polymerase (RdRP; also denoted 3D ^pol) encoded by EV71 could interact with the CARD domain of MDA5 and play a role in inhibition of MDA5-mediated IFN-β promoter activation and mRNA expression. In addition, we found that the 3D ^pol protein encoded by Coxsackievirus B3 could also interact with MDA5 and down-regulated the antiviral signaling initiated by MDA5. These findings indicate that enteroviral RdRP may function as an antagonist against the host antiviral innate immune response.

IMPORTANCE Infection of enterovirus cause severe neurological complications in humans. Human enteroviruses possess various mechanisms to suppress host type I IFN response in infected cells to establish the viral replication. In the present study, we found that the enteroviral 3D ^pol protein, which is viral RNA-dependent RNA polymerase for replicating viral RNA, plays a role in inhibition of MDA5-mediated IFN-β promoter activation. We further demonstrated that enteroviral 3D ^pol protein interacts with the CARD domain of MDA5. These findings indicate that enteroviral RdRP functions as an antagonist against the host antiviral response.