Elucidation of Commensal Bacteria Mechanisms Required for Host Protection

Rockefeller University, New York NY

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Abstract

DESCRIPTION (provided by applicant): The intestinal microbiome is increasingly recognized as an important part of our immune system. Specific members of this consortium are thought to inhibit enteric disease, yet current in vivo models have confounded investigation of bacterial interactions in the intestine due to the complex interdependence between host and microbiota. C. elegans lacks many of these complicating factors and provides a tractable model for the mechanistic exploration of specific bacterial interactions in the intestine. We have identified Enterococcus faecium, a commensal member of the human intestinal microbiota, as an in vivo inhibitor of Salmonella virulence in C. elegans. We hypothesize that E. faecium is acting via a conserved mechanism in worms and mammals to attenuate Salmonella pathogenesis. We aim to identify and characterize the E. faecium factor(s) required for this effect in C. elegans, then analyze the role of these factor(s) in the mouse. Thus, our C. elegans model system provides a bridge between in vitro studies and complex mouse models to investigate the mechanism of a conserved commensal-pathogen interaction. Due to the diverse and considerable influence the intestinal microbiota exerts on host health, the development of probiotic approaches for preventing disease may provide an alternative to antibiotics. Although antibiotics are a mainstay of modern medicine, antibiotic use has fallen under scrutiny in recent years due to the spread of antibiotic resistance in bacterial populations. In addition, antibiotic use has been shown to cause dysbiosis, increasing host vulnerability to gut inflammation and enteric infection. Many members of our intestinal microbiota have been observed to improve host health in various ways. Further development of probiotic therapies, however, will require understanding the roles of individual bacterial species in the complex intestinal environment. The development of C. elegans as a general model for studying intestinal commensal-pathogen interactions could be an important step towards characterizing these interactions, providing an efficient in vivo model system to identify genetic components of commensalism that can then be analyzed in higher animal models.