伪狂犬病毒间质蛋白UL13调控病毒免疫逃逸的作用机制

拮抗宿主抗病毒免疫反应是疱疹病毒实现免疫逃逸的重要策略。环鸟腺苷酸合成酶cGAS是细胞内主要的DNA识别受体，其结合病毒DNA后可激活STING依赖的抗病毒免疫反应。然而,伪狂犬病毒(PRV)能否通过调控cGAS-STING信号通路而实现免疫逃逸未见报道。我们前期发现PRV间质蛋白UL13能够抑制DNA诱导的I型干扰素产生和促进STING蛋白降解，提示UL13可能是一个负向调节cGAS-STING信号的病毒蛋白，但详细作用机制尚不清楚。本项目拟聚焦研究UL13如何调控SITNG蛋白降解以及cGAS-STING信号通路活化和I型干扰素产生，找到UL13作用的靶分子，明确其作用方式，解析其作用机制。同时建立PRV UL13突变毒株感染动物模型，明确UL13对病毒复制的影响和在PRV免疫逃逸中的作用。本项目对于深入理解PRV间质蛋白新功能和阐明PRV免疫逃逸机制具有重要意义。

Alpaherpesviruses employed multiple strategies to antagonize host innate antiviral responses for immune evasion. cGAS is the major cytosolic DNA sensor that recognizes viral DNA to initiate STING-dependent innate antiviral responses. However, it is unknown whether and how PRV targets the cGAS-STING axis for immune evasion. Our preliminary study showed that PRV tegument protein UL13 suppressed DNA-mediated induction of type I IFN and downstream ISGs and promoted protein degradation of STING, indicating that UL13 likely functions as a negative regulator of STING-mediated antiviral responses. In this study, we propose to investigate the molecular mechanisms by which UL13 regulates STING degradation to inhibit production of type I IFN and the in vivo significance of UL13 in immune evasion by PRV. The proposed study will contribute to further understanding of the functions of PRV tegument proteins and the mechanisms of immune evasion and pathogenesis by PRV infection.