Typhoid fever, caused by Salmonella enterica serotype Typhi (S. Typhi), is a major human disease responsible for 21.6 million illnesses and 216,000 deaths annually. The pathogenesis of typhoid fever is incompletely understood due to the lack of suitable animal models for the strictly human-adapted S. Typhi. S. enterica serotype Typhimurium (S. Typhimurium) infection of mice is commonly used to model the pathogenesis of S. Typhi infections in humans. A limitation of this approach is that S. Typhimurium does not cause typhoid fever in humans, but rather causes a localized gastroenteritis. As a result, virulence mechanisms that set typhoid fever apart from human gastroenteritis remain understudied. Experiments proposed in this application are aimed at addressing this important gap in knowledge. Our long-range goal is to elucidate the molecular mechanisms by which Salmonella serotypes manipulate host responses during infection. The objectives of this application are to study the mechanism by which the viaB locus, a S. Typhi-specific DNA region, contributes to host pathogen interaction. Our central hypothesis is that by repressing genes encoding the invasion-associated type III secretion system (T3SS-1) and by activating genes for the biosynthesis of a capsular polysaccharide (the Vi-antigen), the TviA regulatory protein encoded within the viaB locus enables S. Typhi to evade innate immunity, thereby contributing to the development of host responses that distinguish typhoid fever from gastroenteritis. To test our hypothesis, we will determine whether regulation by TviA reduces activation of small Rho GTPases (specific aim 1) and determine the mechanisms of capsule-mediated immune evasion (specific aim 2). Our analysis of S. Typhi specific virulence mechanisms will be useful, and necessary, to understand how the interplay between pathogen and the innate immune system gives rise to responses that distinguish typhoid fever from gastroenteritis. This outcome will be significant, because it will have broad relevance for understanding the molecular virulence mechanisms that distinguish typhoid fever from gastroenteritis.

Public Health Relevance

Typhoid fever is a major human disease syndrome caused by the strictly human adapted Salmonella enterica serotype Typhi. Due to the absence of convenient animal models to study S. Typhi, our understanding of typhoid fever pathogenesis is still incomplete. In this application, we will characterize a S. Typhi-specific virulence factor, te viaB locus, which will provide important new insights into the pathogenesis of typhoid fever.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-A (02))
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Alexander, William A
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University of California Davis
Schools of Medicine
United States
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