Metabolic Interactions between Salmonella and E. coli Nissle 1917

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PROJECT SUMMARY Infection with Salmonella enterica serovar Typhimurium (S. Tm) is a common cause of inflammatory diarrhea. As part of the infection process, S. Tm colonizes the intestinal tract and competes with the microbiota for nutrients. Gut-associated microbial communities antagonize invasion of the ecosystem by enteric pathogens (colonization resistance). The molecular mechanisms of how colonization resistance is achieved remain incompletely understood. Our preliminary data suggest that E. coli Nissle 1917, an E. coli strain with presumed probiotic properties, prevents S. Tm gut colonization and intestinal inflammation by competing efficiently for the respiratory electron acceptor nitrate, a limiting nutrient. We hypothesize that EcN uses one or more siderophore systems to acquire sufficient iron for the iron-sulfur cluster-containing nitrate reductases and to produce high levels of nitrate reductase activity. We will test key aspects of our hypothesis in mouse models of infection and in vitro using a strategic combination of bacterial and host genetics. We will pursue the following specific aims: 1. Investigate how EcN and S. Tm compete for nitrate in the mouse intestine, and 2. Determine whether siderophore-mediated uptake of iron is required for nitrate reductase activity. This work will advance our understanding of how intestinal pathogens, such as S. Tm, and commensal microbes compete for limiting resources in the intestinal tract. These studies are also expected to reveal a molecular property of a probiotic strain, which may help devise novel intervention strategies for Salmonella gastroenteritis.