Salmonella enterica serovar Typhimurium (S. Typhimurium) is a leading cause of gastroenteritis and non- typhoidal bacteremia worldwide. Previous work from our lab has demonstrated that the metabolite, methylthioadenosine (MTA), is able to module the host response to S. Typhimurium. My recent work demonstrated that the molecule serves a second role during S. Typhimurium invasion in which MTA directly suppresses S. Typhimurium virulence by repressing the Salmonella Pathogenicity Island-1 and the flagella regulon. This in turn suppresses the ability for the bacteria to invade cells in the gut, induce inflammation, and results in reduced in vivo virulence. While my recent publication described this phenomenon, the mechanism by which MTA is sensed by S. Typhimurium and suppresses bacterial virulence remains unknown. Further, while we have described that concentrations of MTA change in serum during Salmonella infection, we have not previously explored the possibility that the concentrations of this metabolite change in the gut during a natural model Salmonella infection. If the metabolite is present at different concentrations in the gut during infection, it is unknown whether these changes in concentration have consequences on the bacteria?s ability to successfully colonize the gut. This proposal will address my hypothesis that host MTA can shape disease outcomes by suppressing S. Typhimurium virulence during infection. This would represent a novel example of host- pathogen cross-talk shaping infection outcomes in the gut. The purpose of this grant is to develop a mechanistic understanding of how S. Typhimurium senses and responds to MTA, and to explore the implications of this sensing on host-pathogen cross-talk during infection. To address this, I will measure spatial and temporal MTA regulation along the murine gut and test the ability for host-produced MTA to suppress S. Typhimurium virulence in vivo. I will then pair proteomic, genomic, and transcriptomic approaches to elucidate the molecular mechanisms that enable MTA mediated suppression of S. Typhimurium virulence. Together, these findings will inform the long term goal of this project- which is to to understand how manipulating host and/or bacterial methionine metabolism could be leveraged to improve Salmonella infection outcomes.

Public Health Relevance

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a leading cause of gastroenteritis and bacteremia worldwide, with widespread multi-drug resistance, inadequate diagnostics, and the absence of a vaccine contributing to high global burden of morbidity and mortality. This study seeks to understand a novel host- pathogen cross-talk signaling pathway that suppresses S. Typhimurium virulence and is facilitated by the methionine derived metabolite, methylthioadenosine (MTA). Understanding the role that MTA plays as a cross- kingdom signaling molecule could be leveraged to improve infection outcomes by aiding in the design of novel host directed therapies that increase concentrations of the metabolite, as well as antibiotics that impair the S. Typhimurium methionine metabolism pathway.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Alexander, William A
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Duke University
Schools of Medicine
United States
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