冠状病毒和流感病毒等新发（emerging）RNA病毒易于跨物种传播，感染人体后常导致急性感染和严重症状乃至死亡，但是RNA病毒感染后诱发、逃逸和调控细胞先天免疫反应的机制以及宿主因子在这些过程中的作用仍然不够清楚。申请人前期工作筛选到PTEN等多个宿主因子参与调控宿主细胞I型干扰素反应，本研究将通过国际合作，深入探究PTEN等宿主因子在冠状病毒和流感病毒感染致病过程中对细胞抗病毒先天免疫的调控功能与分子机制，揭示PTEN调控I型干扰素和炎症反应的详细机理，鉴定冠状病毒和流感病毒编码蛋白对相关抗病毒信号通路的对抗作用和机制。这些研究工作将有助于揭示冠状病毒和流感病毒等新发高致病性RNA病毒的感染致病机制以及研发新的RNA病毒防治策略和改进抗病毒治疗方案。

RNA viruses are responsible for a spectrum of significant acute, chronic and emerging infections in humans. These are exemplified by the emerging and re-emerging coronaviruses (such as severe acute respiratory syndrome coronavirus - SARS-CoV, and Middle East respiratory syndrome coronavirus - MERS-CoV) and influenza A viruses (such as IAV H5N1, H7N9 and H1N1), which acutely infect human upper and lower respiratory tracts and cause high rate of morbidity and fatality. However, effective measures are still lacking for control of these emerging and re-emerging life-threatening RNA viruses. The common features of the infection of highly pathogenic CoVs and IAV include induction of strong and inflammatory responses in lower respiratory tract, leading to cytokine storm and severe clinical symptoms. Interactions of these viruses with the adaptive immune system have been studied in great detail, but surprisingly little is known about how these viruses interact with the innate immune system. Recently, we found unexpectedly that the tumor suppressor PTEN plays a pivotal role in IRF3-mediated type I interferon response. In this project, we will make joint effort to characterize the function of PTEN in the activation and regulation of cellular antiviral innate immune responses during the infection of coronavirus and influenza virus, to reveal detailed mechanisms of PTEN regulation in type I interferon response and antiviral innate immunity, to analyze the interplay of PTEN's roles in antiviral innate immunity and tumor suppression, to identify viral components of CoV and IAV involved in the in vivo activation of innate immunity, and to further screen for novel host factors that regulates type I interferon responses during CoV and IAV infection. These studies are expected to advance our understanding in the molecular mechanisms of cellular antiviral innate immunity and facilitate development of novel strategies and measures for the control of RNA virus infections.