Abstract：
The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively4-6. Notably, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.
摘要：
大脑对感染和炎症引起的损伤高度敏感。单纯疱疹病毒1（HSV-1）是一种嗜神经病毒，是引起单纯疱疹病毒脑炎的原因3。尚不清楚神经元特异性抗病毒因子是否控制病毒复制以防止感染和过度炎症反应，从而保护大脑。在这里，我们使用全基因组CRISPR筛选将TMEFF1鉴定为HSV-1限制因子。TMEFF1在中枢神经系统的神经元中特异性表达，不受I型干扰素的调节，控制病毒感染的最著名的先天抗病毒系统。干细胞来源的人神经元中TMEFF1的耗尽导致HSV-1感染后病毒复制和神经元死亡升高。TMEFF1通过与nectin-1和非肌肉肌球蛋白重链IIA和IIB的相互作用，在病毒进入水平上阻断了HSV-1复制周期，它们是病毒-细胞结合和病毒-细胞融合的核心蛋白，分别4-6.值得注意的是,Tmeff1-/-小鼠在脑中表现出对HSV-1感染的易感性增加，但在外周却没有。在大脑中，在神经元中特别观察到病毒载量升高。我们的研究将TMEFF1确定为预防中枢神经系统中HSV-1复制所必需的神经元特异性限制因子。
