This project will examine the role of determinants encoded within the core genome of Enterococcus faecalis in adaptation to survival, growth, and persistence in the mammalian gastrointestinal tract. E. faecalis is a leading cause of hospital-acquired infections whose treatment is impeded by the inherent and acquired antibiotic resistance of the organism, and by its propensity to grow and survive in hostile conditions, and by its ability to transition between commensal and pathogenic lifestyles. Virtually all enterococcal infections are caused by organisms residing in the gut that escape to other body sites. It is well understood that antibiotic treatment or impairment of normal host defenses can result in overgrowth of enterococci in the intestine. However, we know very little about the inherent traits that allow the organism to establish in a healthy intestine, an essential prelude t enterococcal diseases. We will study the model laboratory strain OG1RF in both germ-free mice, and in humanized animals carrying a human-derived gut microbial community. We will use a powerful new genetic screen we have termed Smart TnSeq to identify genetic determinants encoding proteins and small regulatory RNAs that contribute to competitive fitness in the GI tract, and begin to study their functions and mechanisms of action. We will use high-resolution microscopic techniques to examine the behavior of the organisms in vivo, and the expression of genes of interest. The results of this research will include the following: 1) A genome-wide picture of the role of determinants of intestinal fitness will emerge. 2) We will have a much better understanding of preferred sites of colonization of enterococci, and how gene expression is regulated in these favored niches. 3) In the longer term, we may identify new ecologically based strategies, which could prevent enterococcal infections without necessarily killing the bacteria, reducing selection for resistance.

Public Health Relevance

Enterococcus faecalis is a leading cause of hospital-acquired infections that resist antibiotic treatment. In this project we will study how Enterococcus faecali colonizes the gastrointestinal tract. We will use powerful new genetic methods to identify determinants of intestinal colonization ability, and will examine the behavior and gene expression of the organisms in the GI tract at the single-cell level. The results of this research could lead to new ecologically based approaches to prevent or control enterococcal infections without the selective pressure that favors emergence of antibiotic resistance.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Huntley, Clayton C
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University of Minnesota Twin Cities
Schools of Medicine
United States
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