猪塞内卡病毒毒力上升的分子基础

近年来，包括我国在内的全球多个国家爆发猪A型塞内卡病毒（Senecavirus A，SVA）疫情。新发致病性SVA和无毒力SVA原型病毒（SVV-001）有较大遗传差异,但导致SVA毒力上升的分子遗传基础尚未清楚。本项目拟建立无毒力SVA原型毒株(pSVV001)、致病性SVA毒株（pSVA-GX01）及其细胞传代适应弱毒株(pSVA-GXAM)感染性克隆的基础上，分别构建SVA同源强、弱毒株（pSVA-GX01/pSVA-GXAM）和异源强、弱毒株（pSVA-GX01/pSVV-001）基因组片段相互替换的嵌合感染性克隆。对拯救的嵌合病毒进行动物致病性实验，初步确定SVA毒力因子所在区域。然后，进一步构建强、弱毒之间毒力相关的结构域互换或靶位点定点突变的重组病毒,通过动物致病性试验，最终界定SVA的毒力决定因子。本项目研究结果为深入研究SVA的致病机制和研发基因改造的减毒活疫苗奠定基础。

Recently, outbreaks of Senecavirus A (SVA) infection in many counties including China have been reported. The new emerging virulent SVA have great genetic diversity with the prototype SVA strain (SVV-001)，which is avirulent to pig. The molecular determinants responsible for the increased virulence of emerging SVA is unknown. In this proposal，infectious cDNA clones of SVA with different pathogenicity including prototype virus (pSVV-001), emerging virulent SVA (pSVA-GX01) and cell-adapted attunuated strain (pSVA-GXAM) are constructed. Chimeric clones in which genome fragments replace with each other between heterologous viruses（pSVA-GX01 and pSVV-001） and homologous viruses （pSVA-GX01 and pSVA-GXAM）are constructed. The pathogenicity of the recued chimeric viruses on pigs are evaluated to define genome fragment involved in the enhancement of virulence of SVA. And then, chimeric viruses with targeted domain exchanged or recombinant viruses with point mutation are constructed and assessed their pathogenicity on pigs to define the molecular determinants responsible for the increased virulence of emerging SVA. The result of this proposal will lay the foundations for the studying the pathogenic mechanism and the development of the genetic modified live attenuated vaccine of SVA.