Monath T P, Cropp C B, Harrison A K
Lab Invest. 1983 Apr;48(4):399-410.
The mechanism by which neurotropic arboviruses gain access to the central nervous system remains uncertain, although it is generally assumed that viremic infection results in growth across or passive diffusion through brain capillaries. In contrast to the natural reservoir hosts of these arboviruses, clinical hosts (e.g., horses, humans) have viremias of very brief duration and low magnitude. We investigated the question of neuroinvasion in 5- to 6-week-old Syrian hamsters infected with St. Louis encephalitis virus (strain TBH-28). This model shares with the human disease low or undetectable viremia and many clinical and pathoanatomical features. The mortality rate after intraperitoneal inoculation of a moderate viral dose was 88%. No viremia was detectable by a sensitive assay in 31% of the animals. In the remaining hamsters, the mean peak viremia was 1.0 log10 plaque-forming units/0.05 ml and the mean duration 1 to 2 days. There was no correlation between viremia and outcome of infection, length of incubation period, or brain virus titer. Tissue infectivity studies showed a rise in titer in the olfactory neuroepithelium on day 4 postinoculation, then in the olfactory bulbs (day 5 postinoculation), and finally in the remainder of the brain (day 6 postinoculation). Specific immunofluorescence was demonstrated in the bipolar neurons of the olfactory epithelium, their dendrites, and in axon bundles of the olfactory nerves in the submucosa. By electron microscopy, virus particles and associated tubular structures were demonstrated within dendrites, perikarya, and axons of olfactory neurons, and to a lesser extent in macrophages and Bowman's gland cells in the lamina propria. In cells of Bowman's glands large numbers of virions were sequestered within secretory granules. Virus was recovered from nasal washings on day 4 postinoculation. Similar findings were obtained in weanling mice inoculated intraperitoneally with another (mouse-virulent) St. Louis encephalitis viral strain (77V-12908). These data taken together indicate that the olfactory pathway is the principal route of viral entry into the central nervous system. After peripheral inoculation a low-level viremia results in infection of highly susceptible cells in the olfactory neuroepithelium, allowing centripetal axonal transport of virus to the olfactory bulb, whence spread is unimpeded throughout the neuropil of the central nervous system. Infection of Bowman's gland cells in the olfactory mucosa and shedding of virus in nasal mucus may be an adaptation for nonarthropod-borne transmission, a feature of many flaviviruses.
嗜神经性虫媒病毒进入中枢神经系统的机制尚不清楚，尽管一般认为病毒血症感染会导致病毒穿过脑毛细血管生长或被动扩散。与这些虫媒病毒的自然储存宿主不同，临床宿主（如马、人类）的病毒血症持续时间非常短且程度低。我们研究了感染圣路易斯脑炎病毒（TBH - 28株）的5至6周龄叙利亚仓鼠的神经侵袭问题。该模型与人类疾病具有相似之处，即病毒血症低或检测不到，并且具有许多临床和病理解剖学特征。腹腔接种中等剂量病毒后的死亡率为88%。通过灵敏检测，31%的动物未检测到病毒血症。在其余的仓鼠中，平均峰值病毒血症为1.0 log10空斑形成单位/0.05 ml，平均持续时间为1至2天。病毒血症与感染结果、潜伏期长度或脑病毒滴度之间没有相关性。组织感染性研究表明，接种后第4天嗅神经上皮中的滴度升高，然后是嗅球（接种后第5天），最后是脑的其余部分（接种后第6天）。在嗅上皮的双极神经元、其树突以及黏膜下层嗅神经的轴突束中均显示出特异性免疫荧光。通过电子显微镜观察，在嗅神经元的树突、胞体和轴突内发现了病毒颗粒和相关的管状结构，在固有层的巨噬细胞和鲍曼腺细胞中发现的程度较低。在鲍曼腺细胞中，大量病毒粒子被隔离在分泌颗粒内。接种后第4天从鼻腔冲洗液中分离出病毒。在用另一种（对小鼠有致病性的）圣路易斯脑炎病毒株（77V - 12908）腹腔接种的断奶小鼠中也获得了类似的结果。综合这些数据表明，嗅觉途径是病毒进入中枢神经系统的主要途径。外周接种后，低水平的病毒血症导致嗅神经上皮中高度易感细胞感染，使病毒沿轴突向心性运输至嗅球，随后病毒在中枢神经系统的神经毡中不受阻碍地传播。嗅黏膜中鲍曼腺细胞的感染以及病毒在鼻黏液中的排出可能是对非节肢动物传播的一种适应，这是许多黄病毒的一个特征。
