ID2调控抗病毒天然免疫应答的机制研究

天然免疫是机体抗病毒感染的第一道防线。机体为清除侵入的病毒必须启动有效的天然免疫应答，为避免过度天然免疫反应导致免疫病理损伤和清除入侵的病毒后快速恢复细胞内环境稳态，宿主细胞进化出多样的机制以调控天然免疫应答的强度。对宿主抗病毒天然免疫的调控机制的研究近年来是国际上的前沿和热点研究领域。我们的前期工作证明DNA结合抑制分子2（ID2）可负向调控IRF3磷酸化并抑制I型干扰素（IFN-I）产生，但具体分子机制仍不清楚。本课题拟通过制备ID2基因缺陷细胞和条件性敲除小鼠模型，对ID2如何通过TBK1/IKKε-IRF3信号途径调控IFN-β生成的具体分子机制进行更为系统详尽的分析，在机体水平证明ID2在天然免疫应答中的负向调控作用和对2019-nCoV等病毒的复制的调控作用，以期阐明ID2负向调控抗病毒天然免疫的机制，为发现潜在的抗病毒治疗药物靶标提供新的理论基础。

Innate immune response is the first line of defense against viral infection. Host cells recognize viral RNA and DNA through pattern recognition receptors to activate downstream signal transduction pathways, which finally induce the production of antiviral IFN-I. In order to eliminate infected viruses, host cells must initiate effective innate immune responses, and at the same time, control the intensity of innate immune response to avoid immunopathological damage caused by overreaction, and restore homeostasis after eliminating the viruses. Therefore, host cells have evolved a complex and delicate innate immune response regulatory network. In recent years, the research on the regulation mechanism of host antiviral innate immunity is a hot spot in the field of innate immunity, but our understanding is still very limited. Our previous work has proved that ID2 can inhibit the phosphorylation of IRF3 and the production of IFN-I, but the underlying molecular mechanism is not clear. In this study, we intend to systematically and thoroughly analyze the mechanism by which ID2 regulates IFN- TBK1/IKKε-IRF3 signaling pathways, and analyze the negative regulatory role of ID2 in antiviral innate immune response in vivo. We will also investigate the regulatory role of ID2 in the replication of viruses including 2019-nCoV. The findings will expand our understanding of the innate immune regulatory network and may provide potential antiviral therapeutic targets in the future.