Central metabolism of Salmonella in the inflamed gut

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PROJECT SUMMARY 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.