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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI044170-16
Application #
8477653
Study Section
Special Emphasis Panel (ZRG1-IDM-A (02))
Program Officer
Alexander, William A
Project Start
1999-06-15
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
16
Fiscal Year
2013
Total Cost
$417,349
Indirect Cost
$140,961
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
Rivera-Chávez, Fabian; Zhang, Lillian F; Faber, Franziska et al. (2016) Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella. Cell Host Microbe 19:443-54
Song, Jeongmin; Wilhelm, Cara L; Wangdi, Tamding et al. (2016) Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell 164:827-8
Lopez, Christopher A; Miller, Brittany M; Rivera-Chávez, Fabian et al. (2016) Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration. Science 353:1249-53
Vázquez-Torres, Andrés; Bäumler, Andreas J (2016) Nitrate, nitrite and nitric oxide reductases: from the last universal common ancestor to modern bacterial pathogens. Curr Opin Microbiol 29:1-8
Keestra-Gounder, A Marijke; Byndloss, Mariana X; Seyffert, Núbia et al. (2016) NOD1 and NOD2 signalling links ER stress with inflammation. Nature 532:394-7
Bäumler, Andreas J; Sperandio, Vanessa (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85-93
Keestra-Gounder, A Marijke; Tsolis, Renée M; Bäumler, Andreas J (2015) Now you see me, now you don't: the interaction of Salmonella with innate immune receptors. Nat Rev Microbiol 13:206-16
Winter, Sebastian E; Winter, Maria G; Atluri, Vidya et al. (2015) The flagellar regulator TviA reduces pyroptosis by Salmonella enterica serovar Typhi. Infect Immun 83:1546-55
Spees, Alanna M; Kingsbury, Dawn D; Wangdi, Tamding et al. (2014) Neutrophils are a source of gamma interferon during acute Salmonella enterica serovar Typhimurium colitis. Infect Immun 82:1692-7
Atif, Shaikh M; Winter, Sebastian E; Winter, Maria G et al. (2014) Salmonella enterica serovar Typhi impairs CD4 T cell responses by reducing antigen availability. Infect Immun 82:2247-54

Showing the most recent 10 out of 97 publications