Influenza virus host shutoff mechanism

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Virus infection induces a wide range of host defense mechanisms, such as the innate immune response and inflammation. Some viruses express accessory proteins to induce general shutoff of host protein synthesis, which is considered to be one of the major viral strategies to counteract host antiviral activity and immune response. Influenza A virus is one of these viruses and expresses two proteins NS1 and PA-X to induce host shutoff. PA-X is a novel protein found to be expressed from PA mRNA by ribosomal frameshifting. PA-X is composed of an endonuclease domain of PA with a unique C-terminal region. Recent studies including ours indicate that mRNA degradation is the major strategy for host shutoff. The PA-X is more active in shutoff activity than NS-1, and it contains multiple regions involved in specific mRNA degradation. Characterization of a mutant 2009 pandemic H1N1 virus expressing reduced amount of PA-X indicates that PA-X plays a significant role in antagonizing host innate and acquired immune responses. The mechanism of how PA-X induces shutoff is not known. However, a recent study showed that PA-X selectively degrades host RNA polymerase II transcripts, and that pre- mRNAs under 3’-processing are susceptible for PA-X degradation. We also found that PA-X localizes and degrades mRNAs in both the nucleus and cytoplasm, suggesting that PA-X has multiple strategies to capture and degrade pre-mRNAs and mature mRNAs in cells. This project will reveal the mechanism of how PA-X targets and degrades host pre-mRNA in the nucleus (Aim 1), and mature mRNAs in the cytoplasm (Aim 2). Using viruses having various shutoff activities, we will determine the functional interaction between PA-X and NS1 to unveil how IAV adjusts the level of shutoff to create optimum condition for viral replication. Because the shutoff activity directly affects host immune responses, we will test a hypothesis that efficacy of live attenuated vaccine can be improved by suppressing shutoff activity. Overall, the proposed study will provide a foundation for understanding 1) the mechanism by which influenza viruses modulate host gene expression, 2) the mechanism by which viral gene expression is optimized, and 3) the impact of PA-X on viral pathogenicity and host immune response. Upon completion of these studies, we will learn the unique multiple strategy of PA-X in inducing host shutoff in infected cells, and its impact on viral pathogenicity and immune evasion.