Yersinia pestis, the causative agent of plague, has a multicomponent virulence property called the low-Ca2+ response. This consists of at least 13 virulence genes and at least 8 lcr loci that are thought to constitute a regulatory cascade. The lcr loci cause the virulence genes to be regulated in response to environmental cues of Ca2+, nucleotides, and temperature. Long- term goals are to understand the pathway for regulation of virulence genes in the low-Ca2+ response and to learn the mechanisms of action of the virulence proteins.
Aim 1 : lcrB, C, and D will be characterized for their DNA sequences and protein products. Their possible regulatory functions will be determined from sequence analysis and from effects that specific mutations have an RNA expression from other low-Ca2+ response genes.
Aim 2 : Y. pestis mutants will be made, that are deficient in expression of LcrG and V antigen. These proteins are encoded by a low-Ca2+ response operon that has a central role in both regulation and virulence. Testable hypotheses will be developed for the functions of these proteins from each mutant's expression of lcr and virulence genes and from its virulence, growth, and elicitation of pathology in mice.
Aim 3 : 4 lcr gene products will be tested for their ability to function as transcriptional regulators (DNA-binding proteins or modulators of the specificity of RNA polymerase).
Aim 4 : Two low-Ca2+ response-regulated outer membrane proteins called Yops will be tested for ability to serve as protective antigens and for their localization in infected macrophages and mouse tissues. YopM will be tested for its role as a virulence factor that affects platelet aggregation, and YopE will be tested for its effect on cellular natural defense mechanisms. These data will provide insight on how Y. pestis regulates expression of virulence factors in response to environmental cues and how the low-Ca2+ response functions in the pathogenesis of plague. This insight will facilitate the studies of virulence gene regulation and virulence mechanisms in other important human pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI021017-09
Application #
3130916
Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Project Start
1983-09-01
Project End
1994-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Cowan, Clarissa; Philipovskiy, Alexander V; Wulff-Strobel, Christine R et al. (2005) Anti-LcrV antibody inhibits delivery of Yops by Yersinia pestis KIM5 by directly promoting phagocytosis. Infect Immun 73:6127-37
Wulff-Strobel, Christine R; Williams, Andrew W; Straley, Susan C (2002) LcrQ and SycH function together at the Ysc type III secretion system in Yersinia pestis to impose a hierarchy of secretion. Mol Microbiol 43:411-23
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Fields, K A; Straley, S C (1999) LcrV of Yersinia pestis enters infected eukaryotic cells by a virulence plasmid-independent mechanism. Infect Immun 67:4801-13
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Fields, K A; Nilles, M L; Cowan, C et al. (1999) Virulence role of V antigen of Yersinia pestis at the bacterial surface. Infect Immun 67:5395-408
Payne, P L; Straley, S C (1998) YscO of Yersinia pestis is a mobile core component of the Yop secretion system. J Bacteriol 180:3882-90
Williams, A W; Straley, S C (1998) YopD of Yersinia pestis plays a role in negative regulation of the low-calcium response in addition to its role in translocation of Yops. J Bacteriol 180:350-8
Nilles, M L; Fields, K A; Straley, S C (1998) The V antigen of Yersinia pestis regulates Yop vectorial targeting as well as Yop secretion through effects on YopB and LcrG. J Bacteriol 180:3410-20

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