The Aim of this proposal is to understand the function of one of the major vaccinia virus (VV) interferon (IFN)-resistance and neurovirulence genes, E3L. Since VV is the vaccine for smallpox, a potential biowarfare/bioterrorism agent, analysis of this virulence factor may lead to development of safer, more effective vaccines for defense against bioterrorism attacks. In addition, these safer, more effective strains of VV may be valuable for use of VV as a general vaccine vector. Since the E3L gene is highly conserved between VV and all strains of variola virus, the causative agent of smallpox, this work may lead to development of anti-smallpox drugs. The work described in this proposal will continue investigations into defining the roles that the biochemical characteristics of the E3L-encoded proteins play in evasion of the host defenses by VV. Mutants that separately affect each of the known biochemical characteristics associated with E3L-encoded proteins will be prepared and characterized. These well-characterized mutants will then be used to determine the role of each of the biochemical characteristics of E3L in each of the known biological functions of E3L, including pathogenesis in the mouse model. Finally, suppressor mutations will be obtained and analyzed for specific mutations in E3L. The E3L system is unique in allowing analysis of the function of this important virulence gene from the molecular level to the level of pathogenesis in a whole animal. Thus, this work will lead to translation of basic molecular knowledge of E3L function into clinically relevant applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052347-04
Application #
7017107
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Challberg, Mark D
Project Start
2003-07-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$353,122
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
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Jacobs, Bertram L; Langland, Jeffrey O; Kibler, Karen V et al. (2009) Vaccinia virus vaccines: past, present and future. Antiviral Res 84:1-13
Zhang, Ping; Langland, Jeffrey O; Jacobs, Bertram L et al. (2009) Protein kinase PKR-dependent activation of mitogen-activated protein kinases occurs through mitochondrial adapter IPS-1 and is antagonized by vaccinia virus E3L. J Virol 83:5718-25
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Vijaysri, Sangeetha; Jentarra, Garilyn; Heck, Michael C et al. (2008) Vaccinia viruses with mutations in the E3L gene as potential replication-competent, attenuated vaccines: intra-nasal vaccination. Vaccine 26:664-76