Neurobiologie et Développement, UPR3294 CNRS, Institut de Neurobiologie Alfred Fessard, 91198 Gif-sur-Yvette, France.
Adv Virus Res. 2011;79:165-202. doi: 10.1016/B978-0-12-387040-7.00010-X.
Powerful transneuronal tracing technologies exploit the ability of some neurotropic viruses to travel across neuronal pathways and to function as self-amplifying markers. Rabies virus is the only viral tracer that is entirely specific, as it propagates exclusively between connected neurons by strictly unidirectional (retrograde) transneuronal transfer, allowing for the stepwise identification of neuronal connections of progressively higher order. Transneuronal tracing studies in primates and rodent models prior to the development of clinical disease have provided valuable information on rabies pathogenesis. We have shown that rabies virus propagation occurs at chemical synapses but not via gap junctions or cell-to-cell spread. Infected neurons remain viable, as they can express their neurotransmitters and cotransport other tracers. Axonal transport occurs at high speed, and all populations of the same synaptic order are infected simultaneously regardless of their neurotransmitters, synaptic strength, and distance, showing that rabies virus receptors are ubiquitously distributed within the CNS. Conversely, in the peripheral nervous system, rabies virus receptors are present only on motor endplates and motor axons, since uptake and transneuronal transmission to the CNS occur exclusively via the motor route, while sensory and autonomic endings are not infected. Infection of sensory and autonomic ganglia requires longer incubation times, as it reflects centrifugal propagation from the CNS to the periphery, via polysynaptic connections from sensory and autonomic neurons to the initially infected motoneurons. Virus is recovered from end organs only after the development of rabies because anterograde spread to end organs is likely mediated by passive diffusion, rather than active transport mechanisms.
强大的跨神经元示踪技术利用了一些神经嗜性病毒在神经元途径中传播的能力，并将其作为自我放大的标记物。狂犬病病毒是唯一完全特异的病毒示踪剂，因为它仅通过严格的单向（逆行）跨神经元传递在连接的神经元之间传播，从而可以逐步鉴定出越来越高级的神经元连接。在临床疾病发生之前，在灵长类动物和啮齿动物模型中进行的跨神经元示踪研究为狂犬病发病机制提供了有价值的信息。我们已经表明，狂犬病病毒的传播发生在化学突触处，但不是通过缝隙连接或细胞间传播。感染的神经元仍然存活，因为它们可以表达其神经递质并共转运其他示踪剂。轴突运输速度很快，同一突触级别的所有神经元群体都会同时感染，无论其神经递质、突触强度和距离如何，这表明狂犬病病毒受体在中枢神经系统中广泛分布。相反，在周围神经系统中，狂犬病病毒受体仅存在于运动终板和运动轴突上，因为摄取和向中枢神经系统的跨神经元传递仅通过运动途径发生，而感觉和自主神经末梢不会被感染。感染感觉和自主神经节需要更长的潜伏期，因为它反映了从中枢神经系统向周围的离心传播，通过感觉和自主神经元到最初感染的运动神经元的多突触连接。只有在狂犬病发展后才能从终末器官中回收病毒，因为向终末器官的顺行传播可能是通过被动扩散介导的，而不是主动运输机制。
