口蹄疫病毒2B蛋白抑制宿主STING抗病毒作用的机制研究

cGAS-STING信号通路是RNA和DNA病毒感染网络的交集点。本项目前期研究发现口蹄疫病毒（FMDV）感染导致线粒体通透性改变，引起线粒体DNA释放，进而激活cGAS-STING天然免疫信号通路。cGAS或STING的下调表达促进FMDV复制，FMDV 2B通过降低mRNA抑制STING的表达，但其机制不清楚。为了阐明此机制，本项目首先利用敲除小鼠深入探索cGAS和STING对FMDV复制的调控作用，然后筛选2B调控STING mRNA表达靶向的宿主蛋白，并确定调控的分子通路及其机制，进一步鉴定2B发挥调控功能的位点/域。最后，构建2B功能位点突变的重组病毒，通过细胞和宿主水平评价突变和野生毒株复制、致病性等生物学特性的差异，确证鉴定的调控机制。本项目从RNA病毒激活cGAS-STING通路切入，阐明FMDV 2B抑制STING抗病毒功能的机制，为揭示FMDV致病机制提供新的理论依据。

cGAS-STING signaling pathway is the intersection of RNA and DNA virus infection networks. Previous studies of this project found that foot-and-mouth disease virus (FMDV) infection induced mitochondrial DNA release through mitochondrial permeability transition pore, resulting in activation of cGAS-STING mediated innate immune signaling pathway. Down-regulation of cGAS or STING promoted FMDV replication, and FMDV 2B inhibited STING expression at mRNA level. In order to illuminate the molecular mechanism of 2B-mediated inhibition on STING expression, this project will first explore the regulatory effects of cGAS and STING on FMDV replication using knockout mice, then screen the host proteins related to suppression of STING mRNA expression by 2B, as well as determine the molecular pathway and mechanism of transcription regulation by FMDV 2B, and further identify the functional sites or domains in 2B. Finally, to further confirm the identified regulatory mechanism, a recombinant FMDV including 2B functional sites mutantation will be rescued by reverse genetics technique to compare and evaluate the differences of viral replication, pathogenicity, and other biological characteristics at cell and host levels between the mutant and wild strains. This project starts from activation of cGAS-STING pathway induced by FMDV, aiming to elucidate the mechanism of FMDV 2B antagonistic effect on STING-mediated antiviral function, it will lay a foundation for revealing novel pathogenic mechanisms of FMDV.