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Linking Pathogen Virulence, the Microbiota and Disease

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The mechanisms that allow pathogens to colonize the intestine and the indigenous microbiota to inhibit pathogen colonization remain unclear. We found that that germ-free animals are unable to eradicate Citrobacter rodentium, a model for human infections with attaching/effacing (A/E) bacteria. These Gram-negative bacteria are food- and waterborne non-invasive pathogens which attach to and colonize the intestinal tract by inducing characteristic A/E lesions on the intestinal epithelium, leading to transient enteritis or colitis in humans. The genome of A/E pathogens including Enterohemorragic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC) and C. rodentium harbor the locus of enterocyte effacement (LEE) that is critical for bacterial colonization and the ability to cause pathology. We found that early in infection, LEE virulence genes were expressed and required for pathogen growth in conventionally raised but not germ-free mice. LEE virulence gene expression was downregulated during the late phase of infection, which led to relocation of the pathogen to the intestinal lumen where it was out-competed by commensals. The ability of commensals to out-compete C. rodentium was determined, at least in part, by the capacity of the pathogen and commensals to grow on structurally similar carbohydrates. Moreover, we found that dietary carbohydrates can influence the ability of members of the gut microbiota to out-compete the pathogen in the intestine. Our studies indicate the members of the microbiota use metabolic pathways to out-compete pathogens. Furthermore, intestinal pathogens have developed strategies to avoid competition with commensals based on the expression of virulence factors during the early phase of the infection.

Reference:

Kamada N. Kim YG, Sham HP, Vallance BA, Puente JL, Martens EC, Núñez G. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336:1325-1329, 2012.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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