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Work Package 3

Investigating the micro-evolution of E. faecium isolated in a bacteremia context

In the last two decades Enterococcus faecium has emerged as an important nosocomial pathogen that is difficult to treat due to resistance to multiple antibiotics, including ampicillin, aminoglycosides, vancomycin and more recently daptomycin and linezolid1 2. Recently, Ubeda and co-authors3 showed that intestinal domination by VRE preceded bloodstream infection in patients. In this project 10 vancomycin-resistant E. faecium strains, serially isolated from stool samples and blood cultures of three hospitalized patients, are being examined at the level of genome sequence. The central aim of this research is to determine the microevolution of E. faecium within the host as the microbe transitioned to new habitats, and in response to the antibiotics used to control the bacteremia. The analyses will be correlated with meta-information, as in vivo selection for antibiotic resistances or patient related information (antibiotic treatment, cohorting, care team…), collected with those strains.

Work plan

The genomes of the first isolate for each patient will be assembled de novo and serve as a reference. The sequence of subsequent isolates will be compared to the reference and a SNP analysis will be perform, and any other changes in genome sequence will be determined. This will allow us to determine the SNP rate of E. faecium in the host in an infection context, as described previously in the literature for other genus4 5. The role of the identified SNP in the evolution of the cell will be further investigated as needed to explain the acquisition of antibiotic resistance during the treatments used to cure patients of the VRE infection. Acquisition of mobile elements and other genetic variations will be determined. Finally, the relationships between isolates from different patients will be investigated to address the structure of this E. faecium population as well as the pattern of transmission.

References


  1. Willems, R. J., and W. van Schaik. 2009. Transition of Enterococcus faecium from commensal organism to nosocomial pathogen. Future Microbiol 4:1125-1135. 

  2. Arias CA, Contreras GA, Murray BE. Management of multidrug-resistant enterococcal infections. Clin Microbiol Infect. 2010 Jun;16(6):555-62. Review. 

  3. Ubeda C, Taur Y, Jenq RR, Equinda MJ, Son T, Samstein M, Viale A, Socci ND, van den Brink MR, Kamboj M, Pamer EG. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J Clin Invest. 2010 Dec;120(12):4332-41. 

  4. Ford CB, Lin PL, Chase MR, Shah RR, Iartchouk O, Galagan J, Mohaideen N, Ioerger TR, Sacchettini JC, Lipsitch M, Flynn JL, Fortune SM. Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet. 2011 May;43(5):482-6. 

  5. McAdam PR, Holmes A, Templeton KE, Fitzgerald JR. Adaptive evolution of Staphylococcus aureus during chronic endobronchial infection of a cystic fibrosis patient. PLoS One. 2011;6(9):e24301. 

Citation

Please cite all data relating to this initiative (including individual genes and genomes) as:
"Enterococcus Illumina PacBio initiative, Broad Institute (broadinstitute.org)"