病毒感染与复制过程中产生的各类核酸被天然免疫系统的模式识别受体所识别，激活一系列的信号级联反应，诱导I型干扰素等细胞因子的表达。I型干扰素进一步诱导大量的下游基因的表达，进而发挥抗病毒效应。我们发现病毒感染诱导表达的去泛素化酶USP18与介导I型干扰素表达的关键接头蛋白MITA相互作用。已有的研究结果表明USP18 抑制I型干扰素介导的信号通路，但我们发现USP18缺失抑制HSV-1感染诱导的IRF3与NF-kB的活化以及I型干扰素等细胞因子的表达，暗示USP18调控病毒感染诱导I型干扰素表达。在本项目中，我们通过建立Usp18-/-Ifnar1-/- 双敲除小鼠，以及一系列细胞分子生化实验与病毒感染动物模型阐明USP18调控病毒感染诱导I型干扰素表达的分子机制。本项目的研究成果将深化对USP18新功能的认识及对抗病毒天然免疫反应机理的理解，为未来开发抗病毒药物开发提供理论基础。

Viral nucleic acid generated during viral infection and replication is detected by host pattern-recognition receptors and initiates a series of signaling cascades to induce expression of type I interferons (IFNs). Type I IFNs further induce expression of a large array of genes, the products of which promote antiviral responses. We have identified that the viral infection-induced deubiquitinase USP18 interacts with MITA, an essential adaptor protein involved in innate antiviral responses. It has been demonstrated that USP18 inhibits type I IFN-triggered signaling by disrupting the assembly of IFNAR1/2, TYK2/JAK1 and STAT1/2 complex, constituting a negative feedback regulation of type I IFN-mediated antiviral effects. Interestingly, our study shows that USP18 deficiency results in decreased activation of IRF3 and NF-B and subsequent expression of type I IFNs after HSV-1 infection, indicating that USP18 mediates virus-triggered type I IFN induction. In present study, we will establish Usp18-/-Ifnar1-/- double knockout mice and figure out the mechanisms by which USP18 regulates virus-triggered type I IFN signaling. We believe that this study will advance our understanding of the functions of USP18 and the mechanisms of innate antiviral responses, and provide drug target(s) for future treatment of viral infection-related diseases.