I型单纯疱疹病毒下调Cofilin-1促进cGAS降解从而逃逸小胶质细胞抗病毒天然免疫的机制研究

I型单纯疱疹病毒（HSV-1）是人类嗜神经性病毒，其感染能导致疱疹病毒性脑炎（HSE）。小胶质细胞作为脑部免疫细胞，其介导的抗病毒免疫和病毒免疫逃避的平衡是感染致病的关键。前期分析单细胞测序数据发现小胶质细胞高表达Cofilin-1，且体内外感染HSV-1能下调Cofilin-1。敲低Cofilin-1抑制小胶质细胞产生I型干扰素并促进HSV-1复制，过表达Cofilin-1得到相反结果。机制研究发现敲低Cofilin-1导致cGAS降解，且HSV-1感染也促进cGAS降解。据此推测HSV-1通过下调Cofilin-1导致cGAS降解从而逃逸小胶质细胞抗病毒免疫。本研究拟利用小胶质细胞的Cofilin-1敲除小鼠结合基因沉默和过表达等技术从体内外阐明Cofilin-1调控cGAS降解在HSV-1免疫逃逸中的作用及其机理，为Cofilin-1相关通路作为预防或治疗HSE的药靶提供科学依据。

Herpes simplex virus type 1(HSV-1) is an important human neurotropic virus, brain infection of which causes Herpes Simplex Encephalitis (HSE). Microglia are brain-resident macrophages and the balance between microglia-mediated innate antiviral immune response and viral immune evasion is pivotal to viral pathogenesis. Through single-cell RNA-sequencing, we found that Cofilin-1 is highly expressed in microglia. Besides, HSV-1 infection reduced the expression of Cofilin-1 both in vivo. In addition, knockdown of Cofilin-1 reduced the expressions of type I interferons (I-IFNs) and facilitated HSV-1 replication in microglia, whereas overexpressing Cofilin-1 exerted an opposite effect. Mechanically, knockdown of Cofilin-1 led to the degradation of cGAS, which was also observed during HSV-1 infection. Therefore, we speculated that HSV-1 infection inhibits the expression of Cofilin-1 to degrade cGAS to escape from microglial innate antiviral response. In this project, we will explore a series of experiments both in vivo and in vitro, such as microglial Cofilin-1 knockout mice, gene silencing and overexpression, to elucidate the underlying molecular mechanisms and critical roles of Cofilin-1 regulating the degradation of cGAS in HSV-1 infection and immune evasion. Our project will provide the theoretical foundation for the understanding and development of Cofilin-1 associated pathways as therapeutic targets for the prevention or treatment of HSE.