Tissue culture-adapted, mouse brain-adapted and natural street rabies virus (RV) strains such as the silver-haired bat-associated strain (SHBRV) differ greatly in their pathogenicity. Although we have shown that the rabies (RV) glycoprotein (RV G) is a major player in the pathogenesis of rabies, our knowledge of molecular mechanisms involved in the pathogenesis of rabies is still not complete. The cryptic human rabies cases caused by SHBRV typify the gap in our understanding of rabies pathogenesis, which is most likely a multigenic trait involving several RV-encoded proteins and transcriptional elements, as well as host factors. Therefore, we will continue using reverse genetics technology to identify elements of the RV genome that are responsible for the unique ability of this street RV not only to enter the CNS from a peripheral site but also to cause invariably lethal neurological disease. We have shown that RV G induces de novo protein synthesis, along with apoptosis. Based on these findings, we speculate that expression of RV G can cause a dramatic change in cell functions and thereby could play a central role in RV pathogenesis. Consequently, we will investigate the mechanism(s) by which the RV G induces host cell gene expression. Results from these studies will have practical implications for the development of safer and more efficacious live rabies vaccines, and will provide further basic information on rabies virus pathogenicity. This information could lead to the development of novel therapeutic strategies against clinical rabies. This is particularly significant in view of the increasing number of human rabies cases where exposure to RV is not recognized and, therefore, conventional post-exposure prophylaxis is not initiated sufficiently early to be effective.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045097-07
Application #
6847113
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Cassetti, Cristina
Project Start
1999-04-15
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
7
Fiscal Year
2005
Total Cost
$274,750
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Dietzschold, Bernhard; Li, Jianwei; Faber, Milosz et al. (2008) Concepts in the pathogenesis of rabies. Future Virol 3:481-490
Pulmanausahakul, Rojjanaporn; Li, Jianwei; Schnell, Matthias J et al. (2008) The glycoprotein and the matrix protein of rabies virus affect pathogenicity by regulating viral replication and facilitating cell-to-cell spread. J Virol 82:2330-8
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
Blanton, Jesse D; Self, Joshua; Niezgoda, Michael et al. (2007) Oral vaccination of raccoons (Procyon lotor) with genetically modified rabies virus vaccines. Vaccine 25:7296-300
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

Showing the most recent 10 out of 25 publications