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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045097-02
Application #
6170886
Study Section
Special Emphasis Panel (ZRG1-EVR (03))
Program Officer
Meegan, James M
Project Start
1999-04-15
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
2
Fiscal Year
2000
Total Cost
$212,901
Indirect Cost
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Li, Jianwei; McGettigan, James P; Faber, Milosz et al. (2008) Infection of monocytes or immature dendritic cells (DCs) with an attenuated rabies virus results in DC maturation and a strong activation of the NFkappaB signaling pathway. Vaccine 26:419-26
Faber, Milosz; Faber, Marie-Luise; Li, Jianwei et al. (2007) Dominance of a nonpathogenic glycoprotein gene over a pathogenic glycoprotein gene in rabies virus. J Virol 81:7041-7
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Faber, Milosz; Faber, Marie-Luise; Papaneri, Amy et al. (2005) A single amino acid change in rabies virus glycoprotein increases virus spread and enhances virus pathogenicity. J Virol 79:14141-8
Schnell, Matthias J; Tan, Gene S; Dietzschold, Bernhard (2005) The application of reverse genetics technology in the study of rabies virus (RV) pathogenesis and for the development of novel RV vaccines. J Neurovirol 11:76-81
Dietzschold, B; Schnell, M; Koprowski, H (2005) Pathogenesis of rabies. Curr Top Microbiol Immunol 292:45-56
Rupprecht, Charles E; Hanlon, Cathleen A; Blanton, Jesse et al. (2005) Oral vaccination of dogs with recombinant rabies virus vaccines. Virus Res 111:101-5
Faber, Milosz; Bette, Michael; Preuss, Mirjam A R et al. (2005) Overexpression of tumor necrosis factor alpha by a recombinant rabies virus attenuates replication in neurons and prevents lethal infection in mice. J Virol 79:15405-16

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