Viral encephalitis is a major neglected medical problem. Host defense mechanisms against viral infection of the central nervous system (CNS) have long remained unclear. The few previous studies of CNS-specific immunity to viruses in mice in vivo and humans in vitro have focused on the contributions of circulating leukocytes, resident microglial cells and astrocytes, with neurons long considered passive victims of viral infection requiring protection from extrinsic antiviral mechanisms. The last decade has witnessed the gradual emergence of the notion that neurons also combat viruses through cell-intrinsic mechanisms. Forward genetic approaches in humans have shown that monogenic inborn errors of TLR3, IFN-α/β, or snoRNA31 immunity confer susceptibility to herpes simplex virus 1 (HSV-1) infection of the forebrain, whereas inborn errors of DBR1 underlie brainstem infections due to various viruses, including HSV-1. The study of human pluripotent stem cell (hPSC)-derived CNS-resident cells has unraveled known (i.e. TLR3-dependent IFN-α/β immunity) and new (i.e. snoRNA31-dependent or DBR1-dependent immunity) cell-intrinsic antiviral mechanisms operating in neurons. Reverse genetic approaches in mice have confirmed that some known antiviral mechanisms also operate in mouse neurons (e.g. TLR3 and IFN-α/β immunity). The search for human inborn errors of immunity (IEIs) underlying various forms of viral encephalitis, coupled with mouse models in vivo, and hPSC-based culture models of CNS and peripheral nervous system cells and organoids in vitro, should shed further light on the cell-specific and tissue-specific mechanisms of host defense against viruses in the human brain.

中文翻译：

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小鼠和人类对病毒的神经元固有免疫力。


病毒性脑炎是一个被忽视的重大医学问题。长期以来，宿主针对中枢神经系统（CNS）病毒感染的防御机制仍不清楚。先前对小鼠体内和人类体外中枢神经系统特异性病毒免疫的少数研究主要集中在循环白细胞、驻留小胶质细胞和星形胶质细胞的贡献上，神经元长期以来被认为是病毒感染的被动受害者，需要免受外在抗病毒机制的保护。在过去的十年里，神经元也通过细胞内在机制对抗病毒的概念逐渐出现。人类正向遗传学方法表明，TLR3、IFN-α/β 或 snoRNA31 免疫的单基因先天性错误会导致前脑对单纯疱疹病毒 1 (HSV-1) 感染的易感性，而 DBR1 的先天性错误则导致脑干感染，这是由于多种病毒，包括 HSV-1。对人多能干细胞 (hPSC) 衍生的 CNS 驻留细胞的研究揭示了已知的（即 TLR3 依赖的 IFN-α/β 免疫）和新的（即 snoRNA31 依赖或 DBR1 依赖的免疫）细胞内在抗病毒机制的运作在神经元中。小鼠反向遗传方法已证实一些已知的抗病毒机制也在小鼠神经元中发挥作用（例如 TLR3 和 IFN-α/β 免疫）。对各种形式的病毒性脑炎背后的人类先天性免疫错误（IEI）的研究，结合小鼠体内模型，以及基于 hPSC 的中枢神经系统和周围神经系统细胞和类器官的体外培养模型，应该可以进一步阐明该细胞-人脑中宿主防御病毒的特异性和组织特异性机制。