塞内卡病毒是猪的新发病病原，其3C蛋白被鉴定作为水解酶裂解天然免疫信号通路分子而抑制干扰素产生。本项目前期研究揭示了3C蛋白通过其去泛素化酶活性抑制天然免疫的机制，同时还筛选出病毒蛋白VP2与2B具有抑制天然免疫的作用，但机制尚不清楚。针对该科学问题，本项目首先对VP2和2B蛋白抑制天然免疫信号转导的靶蛋白进行鉴定；然后分析VP2和2B对靶蛋白的表达、复合体形成、活化及修饰（泛素化、磷酸化和二聚化等）的影响，鉴定相关调控路径和参与蛋白，揭示其调控与修饰机制；最后，鉴定其抑制天然免疫的功能域或位点，并构建功能域或位点突变的重组病毒，在体外和体内两方面比较重组病毒和野生型病毒抑制天然免疫的功能差异、以及在动物体内复制和致病差异，系统确证拮抗机制。通过本项目研究，解析VP2和2B蛋白抑制天然免疫的机制，为系统阐明塞内卡病毒免疫抑制和致病机制提供新的数据。

Senecavirus A (SVA) is the causative agent of an emerging disease in pigs. The viral protein 3C is identified as a protease that can cleave the adaptor molecules of host innate immune pathway and inhibit interferon production. Our previous study determined that 3C protein also suppresses host innate immune response by blocking the activation of several adaptor molecules of interferon pathway through its deubiquitinase activity. We further identified that the VP2 and 2B proteins of SVA were two new antagonistic factors that can suppress host innate immune response; however, the involved mechanisms remain unknown. In this project, we will identify the adaptor molecules of type I interferon pathway that are targeted by VP2 or 2B, and explore the involved antagonistic mechanisms for VP2 and 2B to block, inhibit or disrupt the functions of the targeted proteins and the involved signal transduction. The antagonistic domains or sites of viral proteins will be determined, and the recombined SVA will be rescued to verify the functions of these antagonistic domains or sites in the cell and animal levels. The data to be generated from this project will clarify the mechanisms of VP2 and 2B proteins to block innate immune response and provide theoretical basis for dissecting the mechanisms of how SVA inhibits host innate immune response.