Enterococci have emerged as leading causes of multidrug resistant hospital infection. Yet they have existed as commensal microbes of everything from insects to man for over 400 million years. Work in the initial period of support showed that multidrug resistant hospital strains have swollen genomes about 25% larger than those of commensal strains. This additional DNA consists largely of a pathogenicity island (PAI) and other fitness islands, antibiotic resistance and other plasmids, transposons, IS elements and phage. We found that the multidrug resistant hospital strains with swollen genomes that emerged in the 70's and later lacked an important defense of the fidelity of the chromosome - the CRISPR locus. Moreover, we showed that in pheromone plasmid containing strains with multiple copies of IS elements, all chromosomal genes could be transferred to a recipient by an Hfr- like plasmid mobilization mechanism. The goal of the competing continuation period is to understand the mechanisms underlying the plasticity and movement of a pathogenicity island in enterococci - the largest mobile element described in the species, and one that harbors most of the know virulence traits. Specifically, data from the initial support period suggested that the E. faecalis PAI evolved by the accretion of modules, possibly mediated by transposases or other site specific recombinases found in the PAI. We now propose to test the integrity and stability of these modules, and determine how genes occurring within a module are functionally linked in disease and colonization environments. Moreover, we propose to determine whether the PAI site specific recombinases are vestigial, or whether they continue to serve an important role in the dissemination of the PAI. These studies will illuminate the mechanisms responsible for the emergence of enterococci as increasingly virulent, multidrug resistant hospital pathogens from roots as benign commensals. Moreover, by understanding the mechanisms involved, we will have the information necessary to quantify the risk of spread of resistance and virulence features among enterococci, and the information needed to understand how widespread antibiotic use selected for microbes with enhanced ability to acquire and accumulate resistance as well as virulence traits.

Public Health Relevance

Multidrug resistant hospital infection is a leading public health concern in the US. Commensal microbes, such as the enterococci, have emerged in the antibiotic era with multiple drug resistances and enhanced virulence. The goals of this project are to determine the mechanisms involved in this transition, and the forces that selected for the outgrowth of these multidrug resistant strains.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072360-07
Application #
8632985
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Huntley, Clayton C
Project Start
2006-12-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
7
Fiscal Year
2014
Total Cost
$405,000
Indirect Cost
$155,000
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Van Tyne, Daria; Gilmore, Michael S (2014) A delicate balance: maintaining mutualism to prevent disease. Cell Host Microbe 16:425-7
Van Tyne, Daria; Gilmore, Michael S (2014) Friend turned foe: evolution of enterococcal virulence and antibiotic resistance. Annu Rev Microbiol 68:337-56
Van Tyne, Daria; Gilmore, Michael S (2014) Virulence Plasmids of Nonsporulating Gram-Positive Pathogens. Microbiol Spectr 2:
Sassoubre, Lauren M; Ramsey, Matthew M; Gilmore, Michael S et al. (2014) Transcriptional response of Enterococcus faecalis to sunlight. J Photochem Photobiol B 130:349-56
Varahan, Sriram; Harms, Nathan; Gilmore, Michael S et al. (2014) An ABC transporter is required for secretion of peptide sex pheromones in Enterococcus faecalis. MBio 5:e01726-14
Gilmore, Michael S; Lebreton, Francois; van Schaik, Willem (2013) Genomic transition of enterococci from gut commensals to leading causes of multidrug-resistant hospital infection in the antibiotic era. Curr Opin Microbiol 16:10-6
Lebreton, Francois; van Schaik, Willem; McGuire, Abigail Manson et al. (2013) Emergence of epidemic multidrug-resistant Enterococcus faecium from animal and commensal strains. MBio 4:
Teixeira, Neuza; Varahan, Sriram; Gorman, Matthew J et al. (2013) Drosophila host model reveals new enterococcus faecalis quorum-sensing associated virulence factors. PLoS One 8:e64740
Van Tyne, Daria; Martin, Melissa J; Gilmore, Michael S (2013) Structure, function, and biology of the Enterococcus faecalis cytolysin. Toxins (Basel) 5:895-911
Palmer, Kelli L; Godfrey, Paul; Griggs, Allison et al. (2012) Comparative genomics of enterococci: variation in Enterococcus faecalis, clade structure in E. faecium, and defining characteristics of E. gallinarum and E. casseliflavus. MBio 3:e00318-11

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