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.

神经上皮是鼻屏障表面，由嗅觉感觉神经元组成，可检测气道中的气味，并通过轴突纤维将这些信息直接传递到大脑。这种屏障表面特别容易受到感染，但呼吸道感染很少引起致命的脑炎，这表明免疫防御高度进化。在这里，我们使用小鼠模型，试图了解先天性和适应性免疫细胞阻止水泡性口炎病毒（VSV）神经侵袭的机制，VSV是一种潜在致命的病毒，在鼻腔感染后利用嗅觉感觉神经元进入大脑。命运图谱研究表明，受感染的中枢神经系统（CNS）神经元被非溶细胞性清除，但从这些神经元中特异性删除主要组织相容性复合体 I 类（MHC I）却意外地对病毒控制没有影响。对病毒特异性 CD8 ⁺ T 细胞中钙信号传导的活体成像研究表明，大脑驻留的小胶质细胞是病毒肽-MHC I 复合物的相关来源。小胶质细胞没有被病毒感染，但在从邻近神经元获取后发现可以交叉呈递抗原。鼻腔感染后，小胶质细胞的耗竭会干扰大脑中 T 细胞钙信号传导和抗病毒控制。总的来说，这些数据表明，小胶质细胞通过将抗原交叉呈递给非溶细胞性清洁神经元的抗病毒 T 细胞，提供了针对神经侵袭性鼻腔感染的前线防御。这种先天防御的破坏可能会使大脑容易受到 VSV 等试图通过鼻子进入中枢神经系统的嗜神经病毒的影响。