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Genome-based characterization of hospital-adapted Enterococcus faecalis lineages

Nature Microbiology volume 1, Article number: 15033 (2016) Cite this article

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Abstract

Vancomycin-resistant Enterococcus faecalis (VREfs) is an important nosocomial pathogen1,2. We undertook whole genome sequencing of E. faecalis associated with bloodstream infection in the UK and Ireland over more than a decade to determine the population structure and genetic associations with hospital adaptation. Three lineages predominated in the population, two of which (L1 and L2) were nationally distributed, and one (L3) geographically restricted. Genome comparison with a global collection identified that L1 and L3 were also present in the USA, but were genetically distinct. Over 90% of VREfs belonged to L1–L3, with resistance acquired and lost multiple times in L1 and L2, but only once followed by clonal expansion in L3. Putative virulence and antibiotic resistance genes were over-represented in L1, L2 and L3 isolates combined, versus the remainder. Each of the three main lineages contained a mixture of vancomycin-resistant and -susceptible E. faecalis (VSEfs), which has important implications for infection control and antibiotic stewardship.

Enterococci are the second and third most frequent cause of nosocomial infections in the USA and Europe, respectively1,2, with Enterococcus faecalis the most commonly isolated species2. Vancomycin is the first-line antimicrobial drug for enterococci with high-level resistance to ampicillin or for patients with penicillin allergy. Vancomycin resistance was first reported in 19883 and has subsequently increased in prevalence. This rise was predominantly due to E. faecium, but E. faecalis accounted for 11% of vancomycin-resistant Enterococcus (VRE) bacteraemias in the UK and Ireland (UK&I) between 2001 and 2013 (http://www.bsacsurv.org). Based on multi-locus sequence typing (MLST)4, it has been determined that vancomycin resistance in E. faecalis has arisen in multiple genetic backgrounds5,6 and is associated with epidemic lineages7. Microbial genome sequencing provides the opportunity to gain a detailed understanding of the molecular basis for hospital adaptation. The first whole-genome sequence of E. faecalis was published in 20038. Subsequent genome studies have compared 18 E. faecalis strains, demonstrating the contribution of mobile genetic elements to the diversity of the species9, and 25 clinical and 7 non-clinical isolates, which were found to be comparable in gene content10. The ability to sequence large bacterial collections means that the molecular epidemiology and gene content of epidemic and sporadic lineages can now be defined systematically.

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Figure 1: Phylogeny of E. faecalis isolates drawn from across the UK and Ireland.
Figure 2: Global population structure of E. faecalis.
Figure 3: Prevalence of virulence and antibiotic resistance genes in the dominant lineages (L1–L3, n = 89) and remainder (n = 79).
Figure 4: Mapping variation in the vancomycin resistance transposon.

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Acknowledgements

The authors thank the Wellcome Trust Sanger Institute library construction, sequence and core informatics teams, the staff at BSAC and the Cambridge Public Health England Microbiology and Public Health Laboratory, and H. Brodrick, A. Cain, D. Pickard, K. Judge and E. Blane for their technical support. The authors acknowledge BSAC for allowing the use of isolates from the BSAC Resistance Surveillance Project. This publication presents independent research supported by the Health Innovation Challenge Fund (HICF-T5-342 and WT098600), a parallel funding partnership between the UK Department of Health and the Wellcome Trust. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health or the Wellcome Trust. This project was also funded by a grant awarded to the Wellcome Trust Sanger Institute (098051). M.E.T. is a Clinical Scientist Fellow supported by the Academy of Medical Sciences, the Health Foundation and the NIHR Cambridge Biomedical Research Centre.

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Authors and Affiliations

  1. Department of Medicine, University of Cambridge, Box 157 Addenbrooke's Hospital, Hills Road, CB2 0QQ, Cambridge, UK

    Kathy E. Raven, Sandra Reuter, Theodore Gouliouris, M. Estée Török & Sharon J. Peacock

  2. Clinical Microbiology and Public Health Laboratory, Public Health England, Box 236, Addenbrooke's Hospital, Hills Road, CB2 0QQ, Cambridge, UK

    Theodore Gouliouris, Nicholas M. Brown & M. Estée Török

  3. Cambridge University Hospitals NHS Foundation Trust, Hills Road, CB2 0QQ, Cambridge, UK

    Theodore Gouliouris, M. Estée Török & Sharon J. Peacock

  4. British Society for Antimicrobial Chemotherapy, Griffin House, 53 Regent Place, B1 3NJ, Birmingham, UK

    Rosy Reynolds & Nicholas M. Brown

  5. North Bristol NHS Trust, Southmead Hospital, BS10 5NB, Bristol, UK

    Rosy Reynolds

  6. Culture Collections, Public Health England, Porton Down, SP4 0JG, Salisbury, UK

    Julie E. Russell

  7. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, Cambridge, UK

    Julian Parkhill & Sharon J. Peacock

  8. London School of Hygiene and Tropical Medicine, WC1E 7HT, London, UK

    Sharon J. Peacock

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Contributions

S.J.P. designed the study. K.E.R. performed bacterial identification, susceptibility testing and DNA extraction, and analysed the data. S.R. assisted with bioinformatic analysis. T.G., R.R., J.E.R., N.M.B. and J.P. contributed materials and data. M.E.T. completed ethical approvals. J.P. and S.J.P. were responsible for supervision and management of the study.

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Correspondence to Kathy E. Raven.

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Raven, K., Reuter, S., Gouliouris, T. et al. Genome-based characterization of hospital-adapted Enterococcus faecalis lineages. Nat Microbiol 1, 15033 (2016). https://doi.org/10.1038/nmicrobiol.2015.33

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