Mutual antagonism between pact and influenza A virus polymerase subunits regulates viral replication and interferon production

Abstract

Interplay between innate antiviral responses and viral antagonism determines the effectiveness of viral replication and viral pathogenicity. Influenza A virus suppresses host innate immunity by various strategies such as expression of viral interferon antagonists NS1 and PB1-F2. We previously demonstrated that PACT protein optimally induces RIG-I-mediated type-I interferon production. A recent report furthered our model and showed that influenza A virus NS1 inhibits PACT/RIG-I-mediated activation of type-I interferon signaling. However, the interaction between PACT and influenza A virus has yet been fully elucidated. In this study, we showed that PACT was associated with influenza A virus polymerase subunits and inhibited viral replication, while all three polymerases, PB2, PB1 and PA, counteracted the PACT/RIG-I-mediated production of type-I interferon. Our data suggested that PACT functions not only to activate interferon signaling, but also to restrict viral replication, possibly through the interaction with viral polymerases. In opposition, polymerase subunits are able to inhibit PACT-mediated induction of type-I interferon and so dampen the host response. Taken together, our findings revealed a new mechanism of virus-host interaction, demonstrating the mutual antagonism between PACT and influenza A virus polymerases. Supported by NSFC (81271852), RGC (ECS 27121515, HKU1/CRF/11G, T11-707/15-R and C7011-15R) and HMRF (12111312, 14130862).