MODE OF ENTRY OF A NEUROTROPIC ARBOVIRUS INTO THE CENTRAL NERVOUS-SYSTEM - REINVESTIGATION OF AN OLD CONTROVERSY

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 48  (4) , 399-410
Abstract
The mechanism by which neurotropic arboviruses gain access to the CNS 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. The question of neuroinvasion in 5-6 wk old Syrian hamsters infected with St. Louis encephalitis virus (strain TBH-28) was studied. This model shares with the human disease low or undetectable viremia and many clinical and pathoanatomical features. The mortality rate after i.p. 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 1-2 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 EM, 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 i.p. with another (mouse-virulent) St. Louis encephalitis viral strain (77V-12908). Evidently, the olfactory pathway is the principal route of viral entry into the CNS. 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 CNS. 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.