PROJECT SUMMARY
Infection with non-typhoidal Salmonella is a significant cause of diarrheal disease worldwide, causing
approximately 150 million illnesses and 60,000 deaths each year. In the gastrointestinal tract, S. Tm encounters
the resident commensal bacteria (gut microbiota). The gut microbiota protects the host against invading
pathogens (colonization resistance) and limits pathogen expansion. Propionate, a short-chain fatty acid
produced by members of the gut microbiota, is predicted to mediate colonization resistance against S. Tm by
down-regulating invasion and inhibiting growth. As a successful pathogen, S. Tm may possess mechanisms to
mitigate the toxic effects of propionate. Discovery of the prpBCDE operon, which enables S. Tm to metabolize
propionate into pyruvate, provided initial insight into the ability of S. Tm to overcome propionate inhibition.
However, it remains unknown under what conditions S. Tm uses the prpBCDE operon to eliminate intracellular
propionate. During infection, the host's inflammatory response provides electron acceptors that allow S. Tm to
metabolize diverse nutrients into carbon sources to support pathogen growth. My data suggests that propionate
serves as a carbon source for S. Tm, specifically during anaerobic respiration when inflammation-derived
electron acceptors are present. In preliminary experiments, I determined that inflammation-derived electron
acceptors also alter propionate-dependent changes in expression of S. Tm invasion machinery. Thus,
inflammation-derived electron acceptors may provide S. Tm with the opportunity to eliminate the inhibitory effects
of propionate and fuel growth during infection. Indeed, my pilot studies demonstrate that propionate metabolism
benefits S. Tm in vivo as a wildtype strain of S. Tm had a growth advantage over a prpC mutant strain in mouse
models of S. Tm gastroenteritis. Therefore, the central hypothesis of this proposal is that S. Tm metabolizes
propionate in the inflamed gut to regulate its invasion and support its luminal growth, ultimately allowing this
pathogen to overcome propionate-dependent colonization resistance. To test this hypothesis, I will use an
innovative combination of commensal members of the gut microbiota and S. Tm mutant strains along with germ-
free and conventional mouse models to explore how S. Tm contends with propionate during infection.
Experiments proposed in Aim 1 will determine if propionate serves as a carbon source to fuel S. Tm growth in
vitro and in vivo. In Aim 2, I will identify if gut inflammation and anaerobic respiration are required for propionate
metabolism to be beneficial to S. Tm during infection. Aim 3 will investigate if propionate metabolism not only
fuels growth by providing a carbon source during respiration but by signaling to S. Tm to decrease invasion. If
successful, this research will challenge the dogma that short-chain fatty acids inhibit Salmonella growth in the
gut. This project will describe how S. Tm mitigates the detrimental effects of propionate by metabolizing this
metabolite into a usable carbon source to fuel growth. Expected findings will provide a deeper understanding of
a novel mechanism used by this bacterial pathogen to evade the intestinal microbiota and establish infection.