Federal Research Institute for Animal Health, Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), 17493, Greifswald-Insel Riems, Germany.
Acta Neuropathol Commun. 2020 Nov 23;8(1):199. doi: 10.1186/s40478-020-01074-6.
The highly neurotropic rabies virus (RABV) enters peripheral neurons at axon termini and requires long distance axonal transport and trans-synaptic spread between neurons for the infection of the central nervous system (CNS). Recent 3D imaging of field RABV-infected brains revealed a remarkably high proportion of infected astroglia, indicating that highly virulent field viruses are able to suppress astrocyte-mediated innate immune responses and virus elimination pathways. While fundamental for CNS invasion, in vivo field RABV spread and tropism in peripheral tissues is understudied. Here, we used three-dimensional light sheet and confocal laser scanning microscopy to investigate the in vivo distribution patterns of a field RABV clone in cleared high-volume tissue samples after infection via a natural (intramuscular; hind leg) and an artificial (intracranial) inoculation route. Immunostaining of virus and host markers provided a comprehensive overview of RABV infection in the CNS and peripheral nerves after centripetal and centrifugal virus spread. Importantly, we identified non-neuronal, axon-ensheathing neuroglia (Schwann cells, SCs) in peripheral nerves of the hind leg and facial regions as a target cell population of field RABV. This suggests that virus release from axons and infected SCs is part of the RABV in vivo cycle and may affect RABV-related demyelination of peripheral neurons and local innate immune responses. Detection of RABV in axon-surrounding myelinating SCs after i.c. infection further provided evidence for anterograde spread of RABV, highlighting that RABV axonal transport and spread of infectious virus in peripheral nerves is not exclusively retrograde. Our data support a new model in which, comparable to CNS neuroglia, SC infection in peripheral nerves suppresses glia-mediated innate immunity and delays antiviral host responses required for successful transport from the peripheral infection sites to the brain.
高度嗜神经性狂犬病病毒（RABV）通过轴突末梢进入外周神经元，需要长距离轴突运输和神经元之间的突触传递来感染中枢神经系统（CNS）。最近对现场 RABV 感染大脑的 3D 成像显示，感染的星形胶质细胞比例非常高，这表明高度毒力的现场病毒能够抑制星形胶质细胞介导的先天免疫反应和病毒消除途径。虽然这对于 CNS 入侵至关重要，但在体内，现场 RABV 在周围组织中的传播和嗜性尚未得到充分研究。在这里，我们使用三维光片和共聚焦激光扫描显微镜来研究在通过自然（肌肉内；后腿）和人工（颅内）接种途径感染后，在清除高容量组织样本中现场 RABV 克隆的体内分布模式。病毒和宿主标志物的免疫染色为 RABV 在中枢神经系统和周围神经中的感染提供了全面的概述，这些感染是通过病毒向心性和离心性传播引起的。重要的是，我们在后腿和面部区域的周围神经中鉴定出非神经元、轴突包绕神经胶质（施万细胞，SCs）作为现场 RABV 的靶细胞群体。这表明病毒从轴突和感染的SCs 中释放是 RABV 体内循环的一部分，可能影响 RABV 相关的周围神经元脱髓鞘和局部先天免疫反应。在颅内感染后在轴突周围包绕髓鞘的SCs 中检测到 RABV 进一步提供了 RABV 顺行传播的证据，突出了 RABV 轴突运输和感染性病毒在周围神经中的传播不仅是逆行的。我们的数据支持了一种新的模型，即在周围神经中，SCs 的感染与 CNS 神经胶质相似，抑制了胶质细胞介导的先天免疫，并延迟了成功从周围感染部位运输到大脑所需的抗病毒宿主反应。
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