Salmonella enterica serotype Typhi causes a severe systemic infection in humans, termed typhoid fever, which is responsible for an estimated 600,000 deaths annually. The pathogenesis of typhoid fever is only poorly understood due to the lack of suitable animal models. S. enterica serotype Typhimurium infection of mice is commonly used as a model to study 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 resulting in diarrhea. The observation that humans infected with S. Typhi or S. Typhimurium develop different disease syndromes (i.e. typhoid fever vs. gastroenteritis) illustrates that some virulence mechanisms important for the pathogenesis of typhoid fever are only present in S. Typhi. The rationale for the proposed research is that a complete understanding of the pathogenesis of typhoid fever will require studies that focus on eliciting S. Typhi-specific virulence mechanisms. 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 TviA, a regulatory protein encoded by the viaB locus, coordinates changes in bacterial gene expression that enable S. Typhi to evade innate immunity, thereby contributing to the development of host responses that distinguish typhoid fever from gastroenteritis. We will test different aspects of our hypothesis and accomplish the objectives of this application by pursuing the following two specific aims: 1. Investigate the mechanisms by which TviA manipulates the interaction of S. Typhi with the innate immune system. 2. Determine the role of the viaB locus in generating disease manifestations that distinguish typhoid fever from infections with non-typhoidal Salmonella serotypes. The proposed studies will take an innovative approach that links clinical observations to molecular virulence mechanisms. By establishing these connections, our studies are expected to demonstrate that TviA- mediated innate immune evasion is a S. Typhi-specific virulence mechanism that can explain several disease manifestations that distinguish typhoid fever from gastroenteritis. This outcome is significant because it will establish a new paradigm in Salmonella pathogenesis, which is expected to have a measurable impact on the field of bacterial pathogenesis.
Typhoid fever is a major human disease syndrome caused by the strictly human adapted Salmonella enterica serotype Typhi. Due to the absence of convenient animals 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, the viaB locus, which will provide important new insights into the pathogenesis of typhoid fever.
| Hiyoshi, Hirotaka; Wangdi, Tamding; Lock, Gabriel et al. (2018) Mechanisms to Evade the Phagocyte Respiratory Burst Arose by Convergent Evolution in Typhoidal Salmonella Serovars. Cell Rep 22:1787-1797 |
| Litvak, Yael; Byndloss, Mariana X; Bäumler, Andreas J (2018) Colonocyte metabolism shapes the gut microbiota. Science 362: |
| 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 |
| 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 |
| 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 |
| 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 |
| Bäumler, Andreas J; Sperandio, Vanessa (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85-93 |
| 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 |
| 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 |
| 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 |
Showing the most recent 10 out of 99 publications
