S-18 : Linking pathogen virulence, the microbiota and immunity

Abstract

The mechanisms that allow pathogens to colonize the intestine and the indigenous microbiota to inhibit pathogen colonization remain unclear. In order to understand the role of the microbiota in controlling pathogen colonization, we have focused our studies on Citrobacter rodentium , a model for human infections by 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. We found that unlike normal mice, germ-free animals are unable to eradicate Citrobacter rodentium from the intestine. 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 the microbiota 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. We will show additional studies that provide an understanding for how the host immune system regulates pathogen virulence and cooperatively acts with the microbiota to control pathogen eradication in the intestine will be discussed.