Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Department of Immunology, Duke University School of Medicine, Durham, NC, USA.
Sci Immunol. 2020 Jun 5;5(48). doi: 10.1126/sciimmunol.abb1817.
The neuroepithelium is a nasal barrier surface populated by olfactory sensory neurons that detect odorants in the airway and convey this information directly to the brain via axon fibers. This barrier surface is especially vulnerable to infection, yet respiratory infections rarely cause fatal encephalitis, suggesting a highly evolved immunological defense. Here, using a mouse model, we sought to understand the mechanism by which innate and adaptive immune cells thwart neuroinvasion by vesicular stomatitis virus (VSV), a potentially lethal virus that uses olfactory sensory neurons to enter the brain after nasal infection. Fate-mapping studies demonstrated that infected central nervous system (CNS) neurons were cleared noncytolytically, yet specific deletion of major histocompatibility complex class I (MHC I) from these neurons unexpectedly had no effect on viral control. Intravital imaging studies of calcium signaling in virus-specific CD8 T cells revealed instead that brain-resident microglia were the relevant source of viral peptide-MHC I complexes. Microglia were not infected by the virus but were found to cross-present antigen after acquisition from adjacent neurons. Microglia depletion interfered with T cell calcium signaling and antiviral control in the brain after nasal infection. Collectively, these data demonstrate that microglia provide a front-line defense against a neuroinvasive nasal infection by cross-presenting antigen to antiviral T cells that noncytolytically cleanse neurons. Disruptions in this innate defense likely render the brain susceptible to neurotropic viruses like VSV that attempt to enter the CNS via the nose.
神经上皮是鼻腔屏障表面的一部分，由嗅感觉神经元组成，这些神经元可以检测到气道中的气味，并通过轴突纤维将这些信息直接传递到大脑。这个屏障表面特别容易受到感染，但呼吸道感染很少导致致命的脑炎，这表明存在高度进化的免疫防御机制。在这里，我们使用小鼠模型，试图了解先天免疫和适应性免疫细胞阻止水疱性口炎病毒（VSV）神经入侵的机制，VSV 是一种潜在致命的病毒，它通过鼻腔感染后利用嗅感觉神经元进入大脑。命运图谱研究表明，感染的中枢神经系统（CNS）神经元被非细胞溶解方式清除，但这些神经元中主要组织相容性复合体 I 类（MHC I）的特异性缺失出人意料地对病毒控制没有影响。病毒特异性 CD8 T 细胞钙信号的活体成像研究反而揭示了脑驻留小胶质细胞是病毒肽-MHC I 复合物的相关来源。小胶质细胞本身不被病毒感染，但在从相邻神经元获取抗原后，被发现可以交叉呈递抗原。小胶质细胞耗竭会干扰 T 细胞在鼻腔感染后的钙信号和抗病毒控制。总的来说，这些数据表明，小胶质细胞通过交叉呈递抗原给抗病毒 T 细胞来提供针对鼻内感染的一线防御，从而非细胞溶解方式清除神经元。这种先天防御的破坏可能使大脑容易受到试图通过鼻子进入中枢神经系统的神经嗜性病毒（如 VSV）的侵害。
