Center of Evolutionary and Theoretical Immunology, Biology Department, University of New Mexico, Albuquerque, NM 87131.
Biology Department, University of New Mexico, Albuquerque, NM 87131.
Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12428-12436. doi: 10.1073/pnas.1900083116. Epub 2019 Jun 3.
The nervous system regulates host immunity in complex ways. Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with pathogens; however, OSNs' ability to detect danger and initiate immune responses is unclear. We report that nasal delivery of rhabdoviruses induces apoptosis in crypt OSNs via the interaction of the OSN TrkA receptor with the viral glycoprotein in teleost fish. This signal results in electrical activation of neurons and very rapid proinflammatory responses in the olfactory organ (OO), but dampened inflammation in the olfactory bulb (OB). CD8α cells infiltrate the OO within minutes of nasal viral delivery, and TrkA blocking, but not caspase-3 blocking, abrogates this response. Infiltrating CD8α cells were TCRαβ T cells with a nonconventional phenotype that originated from the microvasculature surrounding the OB and not the periphery. Nasal delivery of viral glycoprotein (G protein) recapitulated the immune responses observed with the whole virus, and antibody blocking of viral G protein abrogated these responses. Ablation of crypt neurons in zebrafish resulted in increased susceptibility to rhabdoviruses. These results indicate a function for OSNs as a first layer of pathogen detection in vertebrates and as orchestrators of nasal-CNS antiviral immune responses.
神经系统以复杂的方式调节宿主免疫。脊椎动物嗅觉感觉神经元 (OSN) 位于与病原体直接接触的位置；然而，OSN 检测危险并引发免疫反应的能力尚不清楚。我们报告称，通过 OSN TrkA 受体与鱼类杆状病毒糖蛋白的相互作用，鼻内递送弹状病毒会诱导隐窝 OSN 凋亡。该信号导致神经元的电激活和嗅觉器官 (OO) 中非常迅速的促炎反应，但嗅球 (OB) 中的炎症减轻。CD8α 细胞在鼻内病毒递送后几分钟内渗透到 OO 中，TrkA 阻断，但不是 caspase-3 阻断，可消除这种反应。浸润的 CD8α 细胞是 TCRαβ T 细胞，具有非传统表型，源自 OB 周围的微血管，而不是外周。鼻内递送病毒糖蛋白 (G 蛋白) 可再现与整个病毒观察到的免疫反应，并且病毒 G 蛋白的抗体阻断可消除这些反应。斑马鱼隐窝神经元的消融导致对弹状病毒的易感性增加。这些结果表明 OSN 作为脊椎动物中病原体检测的第一道防线，并作为鼻-中枢神经系统抗病毒免疫反应的协调者发挥作用。
