Yersinia pestis, an etiological agent of the acute diseases bubonic and pneumonic plague and one of the most devastating epidemic-causing bacteria experienced by mankind, is now classified as a re-emerging human pathogen by the WHO. The potential for contagion, lack of an effective vaccine, and emergence of multiple antibiotic- resistant strains place Y. pestis at the top of the U.S. select agent list as a potential bioterrorism agent. Our long-term goal is to elucidate molecular mechanisms underlying the acute bacterial infectious process of Y. pestis . The more immediate objective is to identify and evaluate new and existing antigens of Y. pestis to develop a new generation plague vaccine. The complete genome sequence of Y. pestis is now known.
Four aims are proposed.
In Aim 1 we will prepare a Braun/murein lipoprotein (lpp)-minus mutant of Y. pestis , based on our recent data that the patented Ipp isogenic mutants of Salmonella Typhimurium and of Y pseudotuberculosis are avirulent in mice and provide protection against challenge with the wild-type bacterium. We will examine these mutants for immunological responses in mice to develop a live attenuated Y. pestis vaccine or use Y. pseudotuberculosis as a carrier for Y. pestis antigens.
Aim 2 will identify differentially or exclusively expressed genes (potentially virulence-associated) of Y. pestis by genomics and proteomics to evaluate new antigens for use in a recombinant subunit plague vaccine.
Aim 3 will examine the virulence potential of selected in vivo-expressed genes of Y. pestis by developing isogenic mutants and evaluating them for lethality in a mouse model and assess selected antigens'ability to provide immunity against Y. pestis challenge.
Aim 4 will examine potential use of the Ipp-minus mutants of Y. pseudotuberculosis and S. Typhimurium as carriers to deliver Y. pestis antigens by expressing selected genes either from a plasmid under an inducible promoter and/or chromosome of attenuated Y. pseudotuberculosis/S. Typhimurium or by DMA vaccination. Alternatively, a vaccine strain of S. Typhi (Ty21a) could also be used. We believe these multiple approaches will identify candidate antigens for a use in a new, efficacious plague vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064389-06
Application #
7777319
Study Section
Special Emphasis Panel (ZRG1-IMM-G (03))
Program Officer
Mukhopadhyay, Suman
Project Start
2005-02-01
Project End
2011-05-19
Budget Start
2010-02-01
Budget End
2011-05-19
Support Year
6
Fiscal Year
2010
Total Cost
$272,881
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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