口蹄疫病毒结构蛋白 VP3 调控 β 干扰素信号通路的分子机制

The induction of type I interferons by viral infection has been a hot topic in innate immune responses against viral infection. During the foot-mouth disease virus (FMDV) infection of host cells, it is unclear whether the FMDV VP3 structure protein induces or inhibits type I interferons. Previously studies found that FMDV VP3 inhibited the expression of type I interferons and its downstream genes. To elucidate the molecular mechanism underlying inhibition of interferon-beta (IFN-β) by FMDV VP3, we will probe the interaction between FMDV VP3 protein and IFN-β signaling pathway proteins and its interacting domains or key sites using co-immunoprecipitation. Further we will determine whether the FMDV VP3 protein affects deubiquitination or immune complex formation of its interacting proteins. Then by rescuing functional mutant virus of FMDV VP3 failing to interact with IFN-β signaling pathway, we will confirm the role of the above interaction in the IFN-β signaling pathway. This study will provide critical information on inhibition of innate immune by FMDV and a theoretical basis to improve antigen and develop vaccines inducing early immune response as well as exploit a strategy for FMD control.

病毒感染诱导或抑制 I 型干扰素表达的过程一直是抗病毒天然免疫研究的热点问题。口蹄疫病毒（FMDV）在感染宿主细胞的过程中，其 VP3 结构蛋白诱导或抑制 I 型干扰素表达的机制尚不清楚。我们的前期研究发现，FMDV 结构蛋白VP3 抑制 β 干扰素 (IFN-β) 及其信号通路下游效应分子的表达。为了阐明 VP3 调控 IFN-β 信号通路的分子机制，本项目将利用免疫共沉淀 (Co-IP) 技术鉴定 VP3 与 IFN-β 信号通路相互作用的分子机制及其互作区域或位点；并确定 VP3 对其互作的 IFN-β 信号通路分子复合体和泛素化的影响；拯救出 VP3 失去抑制 IFN-β 信号通路的功能位点突变的 FMDV，检测其对 IFN-β 信号通路的影响。本研究为全面揭示 FMDV 抑制天然免疫提供有力证据，为改善抗原和制备早期免疫应答疫苗奠定理论基础，为制定科学的防控策略提供理论依据。

口蹄疫是由口蹄疫病毒引起的感染偶蹄类动物的传染性疾病。口蹄疫病毒可以通过拮抗天然免疫而逃脱宿主的I型干扰素的应答，例如口蹄疫病毒的L和3C蛋白。我们鉴定了口蹄疫病毒的结构蛋白VP3能够抑制beta干扰素的产生。口蹄疫病毒VP3蛋白能够抑制仙台病毒诱导的IFR3/MDA5/RIG-I的表达。免疫共沉淀实验证实VP3与VISA有相互作用。口蹄疫病毒VP3蛋白通过抑制VISA的mRNA进而抑制它的表达。总之，我们揭示了口蹄疫病毒通过VP3蛋白逃逸天然免疫的机制。