Salmonella enterica serotype Typhi causes a severe systemic infection in humans, termed typhoid fever, which is responsible for some 600,000 deaths annually. Our long-range goal is to elucidate the molecular mechanisms involved in the pathogenesis of typhoid fever. The objectives of this application are to study the mechanism by which a S. Typhi-specific virulence factor, the Vi capsular antigen, contributes to host pathogen interaction. Our central hypothesis is that expression of the Vi-antigen blocks innate immune recognition of a subset of pathogen associated molecular patterns (PAMPs), thereby altering interaction with host cells. We will test different aspects of our hypothesis and accomplish the objectives of this application by pursuing the following two specific aims. 1. Determine whether expression of the Vi capsular antigen can block Toll-like receptor (TLR) recognition of known S. Typhi PAMPs. 2. Determine whether expression of the Vi antigen affects phagocytosis, phagosome maturation and survival of S. Typhi in human macrophages. The proposed work is innovative because it challenges the dogma that expression of a polysaccharide capsule serves mainly to avoid phagocytosis. It is our expectation that our approach will establish the role of the Vi antigen in evasion of TLR recognition during typhoid fever. This outcome will be significant because it promises to establish a new paradigm in host pathogen interaction that may be applicable to a number of other capsulated pathogens. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI065534-01
Application #
6954272
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Alexander, William A
Project Start
2005-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$189,375
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Godinez, Ivan; Haneda, Takeshi; Raffatellu, Manuela et al. (2008) T cells help to amplify inflammatory responses induced by Salmonella enterica serotype Typhimurium in the intestinal mucosa. Infect Immun 76:2008-17
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Raffatellu, Manuela; Santos, Renato L; Chessa, Daniela et al. (2007) The capsule encoding the viaB locus reduces interleukin-17 expression and mucosal innate responses in the bovine intestinal mucosa during infection with Salmonella enterica serotype Typhi. Infect Immun 75:4342-50
Nuccio, Sean-Paul; Baumler, Andreas J (2007) Evolution of the chaperone/usher assembly pathway: fimbrial classification goes Greek. Microbiol Mol Biol Rev 71:551-75
Nuccio, Sean-Paul; Chessa, Daniela; Weening, Eric H et al. (2007) SIMPLE approach for isolating mutants expressing fimbriae. Appl Environ Microbiol 73:4455-62
Tukel, Cagla; Akcelik, Mustafa; de Jong, Maarten F et al. (2007) MarT activates expression of the MisL autotransporter protein of Salmonella enterica serotype Typhimurium. J Bacteriol 189:3922-6

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