中东呼吸综合征冠状病毒(MERS-CoV)是一种新型且有高致死率的冠状病毒，前期研究初步表明MERS-CoV附属蛋白ORF4b抑制MDA5、RIG-I、MAVS、IKKε、TBK1、IRF3和IRF7激活的干扰素产生，并可以与MDA5、TBK1和IKKε结合，破坏MAVS与IKKε的形成复合物，抑制磷酸化形式的IRF3产生，而ORF4b在细胞质中拮抗干扰素的分子机制有待进一步明确。核定位信号去除的ORF4b不能抑制IRF3/7激活的干扰素产生，提示ORF4b在细胞核内也存在着未知拮抗干扰素产生的分子机制。本课题拟在前期结果基础上，构建ORF4b缺失的感染性克隆，并进行两方面研究：首先明确ORF4b在细胞质中拮抗干扰素产生的具体机制，其次重点研究ORF4b在细胞核中抑制IRF3激活的干扰素产生的分子机制，全面阐述ORF4b拮抗干扰素产生的分子机制，为寻找潜在有治疗作用的分子靶点提供理论基础。

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel and highly pathogenic human coronavirus, previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response activated by MDA5、RIG-I、MAVS、IKKε、TBK1、IRF3 and IRF7, further demonstrated that ORF4b could specifically bind to MDA5, TBK1 and IKKε, suppress the molecular interaction between MAVS and IKKε, and inhibit IFN regulatory factor 3 phosphorylation, but the exact mechanism of ORF4b function in cytoplasm is unclear. Further analysis showed that deletion of the nuclear localization signal of ORF4b abrogated its ability to inhibit IRF3/IRF7-induced activation of IFN-β, suggesting that there is an unknown mechanism that ORF4b could inhibit the induction of IFN-β in nucleus. In this study, we mainly use MERS-CoV infectious clone to study the exactly mechanism of MERS-CoV ORF4b both in cytoplasm and in the nucleus, and provide theoretical basis for detecting potential molecular therapeutic targets.