Infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Tm) is a common cause of inflammatory diarrhea. Intriguingly, intestinal inflammation drives an expansion of the S. Tm population in the gut lumen. The molecular mechanisms that support S. Tm colonization of the intestinal tract remain incompletely understood. Our central hypothesis is that the inflamed gut constitutes a peculiar nutritional environment that enables S. Tm to outgrow obligate anaerobic commensal bacteria. We have recently demonstrated that during the acute phase of the infection, neutrophil-derived electron acceptors facilitate an oxidative central metabolism in S. Tm. In this application, we hypothesize that S. Tm relies on a branched TCA cycle for initial gut colonization. In particular, tartaric acid, produced through oxidation of microbiota-liberated sugars, supports fumarate reduction in the branched TCA cycle. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) determine how utilization of D- and L-tartrate contributes to growth of S. Tm in the lumen of the mammalian large intestine, 2.) determine the origin of tartrate during S. Tm infection, and 3.) investigate the regulation of tartrate utilization genes in vitro and in vivo. This work will advance our understanding of how intestinal pathogens, such as S. Tm, adapt their carbon and energy metabolism to colonize the mammalian intestinal tract. We envision that a better understanding of the mechanisms by which S. Tm outgrows competing microbes during inflammation will aid the development of new and innovative approaches for treatment.

Public Health Relevance

Non-typhoidal Salmonella serotypes are a common cause diarrheal disease in the United States, with a cost of $0.5 to $2.3 billion per year due to lost productivity and the cost of medical care. This application will support studies on how Salmonella colonizes the mammalian intestinal tract and causes disease symptoms. A better understanding of the molecular mechanisms that influence bacterial colonization is expected to aid in the development of new intervention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI118807-06
Application #
9885435
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
2015-05-01
Project End
2024-11-30
Budget Start
2019-12-18
Budget End
2020-11-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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