To date, the molecular mechanisms involved in the pathogenesis of either canine street rabies or the newly emerging infections with the silver- haired bat-associated rabies virus strain (SHBRV) remain obscure. The purpose of this proposal is to delineate these mechanisms with particular focus on interactions between rabies virus and neurons. Our preliminary data reveal that tissue cultured-adapted, mouse brain- adapted and natural street rabies virus strains, which differ greatly in their pathogenicity in vivo, also differ markedly in the expression levels of the rabies virus structural proteins, in particular the glycoprotein (G), in cultured neurons. Surprisingly, the pathogenicity index of a particular rabies virus strain correlates inversely with the expression of the viral G protein on the surface of the infected neuron. One possibility is that this results in a self-limiting infection by preventing the transport of the rabies virus nucleoprotein complex into the periphery of the neuron, i.e., into neuronal processes, and hence axonal spread of the virus. In infections with highly pathogenic rabies virus strains such as SHBRV, the expression of the G protein in neurons is minimal and apoptosis does not occur until the infection has spread to the next uninfected neuron. We intend to investigate the mechanism(s) involved in the regulation of viral gene expression in neurons and identify proteins associated with the pathogenicity of street rabies virus strains in order to better understand the pathogenesis of human rabies, especially the cryptic human rabies cases caused by SHBRV that have occurred recently in North America.
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