Infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Tm) results in acute inflammatory diarrhea. S. Tm invades the intestinal epithelium and replicates in the tissue phagocytes, triggering a potent mucosal inflammatory response aimed at clearing the invading bacteria. Intriguingly, intestinal inflammation results in an expansion of the S. Tm population in the gut lumen. The molecular mechanisms underlying the outgrowth of S. Tm over the indigenous microbiota remains largely unknown. Our central hypothesis is that the inflamed gut constitutes a peculiar nutritional environment that enables S. Tm to outgrow competing commensal microbes. We will test key aspects of our hypothesis by pursuing the following specific aims: 1.) Determine the contribution of the electron donor formate to growth of S. Tm in the inflamed gut lumen and test the working hypothesis that inflammation perturbs syntrophic relationships between formate-producing and -consuming microbes, allowing S. Tm to access the formate pool during growth in the inflamed gut. 2.) Determine how host-derived electron acceptors alter regulation of the TCA cycle and explore potential consequences. Successful completion has a strong potential to have a high impact on gastroenteritis research by providing a novel concept, i.e. that an enteric pathogen exploits metabolites from both, the host (electron acceptors) and the microbiota (fermentation end products). 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.
Salmonella serotypes are the most common cause of death and hospitalization from diarrheal disease and the leading cause of food-borne disease outbreaks in the United States, generating between $0.5 billion to $2.3 billion in costs for medical care and lost productivity annually in the US. Research proposed in this application will support pioneering studies on molecular mechanisms that control bacterial colonization and host transmission. The proposed studies will drive knowledge about Salmonella gastroenteritis to a higher level by providing new mechanistic insights into pathogenesis and by facilitating the development of new intervention strategies through science.
