人肠道病毒2C蛋白通过抑制RNA识别通路调控宿主天然免疫的机制研究

近年来，柯萨奇病毒A组6型（CA6）逐渐成为手足口病的三大病原体之一。但目前国内外对CA6的致病机制及其相关蛋白的功能研究还鲜有报道。申请人此前研究表明，CA6-2C蛋白诱导细胞死亡的能力与病毒释放量有较大关联。本项目中，前期结果表明CA6-2C可以抑制IFN-β的启动子活性，而该抑制是通过调控RNA识别受体RIG-I及MDA5的蛋白水平来实现的。因此，我们拟从蛋白、RNA及启动子水平探讨CA6-2C通过RIG-I及MDA5来调控干扰素水平，从而对抗宿主天然免疫的机制。同时，研究影响CA6-2C调控RIG-I及MDA5蛋白水平的氨基酸突变体。探讨2C蛋白对IFN-β水平的调控是否在人肠道病毒属中具有广谱性。最后，揭示CA6-2C通过调控IFN-β水平对病毒感染复制的影响。相关成果将阐明2C蛋白通过抑制RNA识别通路的干扰素水平对抗宿主天然免疫，为新型抗手足口病药物研发提供新思路和潜在靶点。

Recently, coxsackievirus A6 (CA6) had gradually become one of the three major pathogens of HFMD. However, the pathogenic mechanism of CA6 and functions of the related proteins have rarely been reported in the world. In our previous study, we found that the ability of CA6-2C protein to induce cell death is strongly associated with viral release. In the present project, our preliminary results indicate that CA6-2C can inhibit the IFN-β promoter activity, which is achieved by regulating the protein expression levels of RNA recognition receptors RIG-I and MDA5. Therefore, we intend to further explore the molecular mechanism of CA6-2C protein on regulation of host innate immunity through RIG-I and MDA5 from protein, RNA and promoter levels. At the same time, to study the functional regions and amino acid mutants of CA6-2C protein by which to affect the regulation of RIG-I and MDA5 protein levels. Subsequently, to investigate whether the regulation of IFN-β levels by 2C protein is conservative in human enterovirus genus. Finally, we will explore the important role of CA6-2C protein on regulation of IFN-β levels in viral infection and replication cycles. These relevant results will clarify that 2C protein antagonizes host innate immunity by inhibiting the RNA sensing pathway, and provides new insight and potential targets for novel anti-HFMD drugs development.