Induction and inhibition of cell innate immunity by influenza virusGCOE Program Seminar(Global Education Seminar)

The cytoplasmic antiviral sensor RIG-I plays a key role in RNA virus recognition and initiation of the innate immune response. Activation of RIG-I by immunostimulatory RNA leads to its association with mitochondrially localiz，adaptor MAVS and downstream signaling resulting in production of type I IFN and other proinflamatory cytokines. Immunoprecipitation of RIG-I/RNA complexes from virus infected cells allowed us to analyze RNA molecules which specificalIy interact with RIG-I during the course of viral infection. Unbiased deep sequencing analysis along with biochemical characterization of isolated RNA revealed specific viral sequences associated with RIG-I in Sendai and influenza virus infected cells. However， in influenza virus infected cells, induction of IFN is prevented due to expression of the viral NS 1 protein. This multi-functional protein interacts with and inhibits different components of the cell machinery， including TRIM25 and CPSF30， preventing an optimal expression of IFN in virus-infected cells. TRIM25 is an E3 ubiquitin ligase required for optimal activation of RIG-I， while CPSF30 is required for the processing of cellular mRNAs. Mutations that affect binding of NS1 to TRIM25 result in recombinant influenza viruses unable to prevent induction of IFN responses. These NS1 mutant viruses are restricted in their ability to replicate due to the host IFN-mediated antiviral response.