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Molecular Tracing of the Emergence, Adaptation, and Transmission of Hospital-Associated Methicillin-Resistant Staphylococcus Aureus

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Molecular Tracing of the Emergence, Adaptation, and Transmission of Hospital-Associated Methicillin-Resistant Staphylococcus Aureus Molecular tracing of the emergence, adaptation, and transmission of hospital-associated methicillin-resistant Staphylococcus aureus Paul R. McAdama, Kate E. Templetonb, Giles F. Edwardsc, Matthew T. G. Holdend, Edward J. Feile, David M. Aanensenf, Hiba J. A. Bargawif, Brian G. Sprattf, Stephen D. Bentleyd, Julian Parkhilld, Mark C. Enrightg, Anne Holmesa, E. Kirsty Girvanc, Paul A. Godfreyh, Michael Feldgardenh, Angela M. Kearnsi, Andrew Rambautj,k, D. Ashley Robinsonl, and J. Ross Fitzgeralda,1 aThe Roslin Institute and Edinburgh Infectious Diseases, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH259RG, United Kingdom; bMicrobiology, Royal Infirmary of Edinburgh, Edinburgh EH164SA, United Kingdom; cScottish MRSA Reference Laboratory, National Health Service Greater Glasgow and Clyde, Stobhill Hospital, Glasgow G213UW, United Kingdom; dThe Wellcome Trust Sanger Institute, Cambridge CB101SA, United Kingdom; eDepartment of Biology and Biochemistry, University of Bath, Bath BA27AY, United Kingdom; fDepartment of Infectious Disease Epidemiology, Imperial College London, London W21PG, United Kingdom; gAmpliPhi Biosciences Corp., Colworth Science Park, Bedfordshire MK441LQ, United Kingdom; hBroad Institute of Massachusetts Institute of Technology and Harvard, Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142; iMicrobiology Services Colindale, Health Protection Agency, London NW9 5EQ, United Kingdom; jInstitute of Evolutionary Biology, Ashworth Laboratories, University of Edinburgh, Midlothian EH3 9JT, United Kingdom; kDivision of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, MD 20892; and lDepartment of Microbiology, University of Mississippi Medical Center, Jackson, MS 39216 Edited by Richard P. Novick, New York University School of Medicine, New York, NY, and approved April 6, 2012 (received for review February 19, 2012) Hospital-associated infections caused by methicillin-resistant Staphy- methicillin-sensitive phage type 80/81 clone in the 1950s and 1960s, lococcus aureus (MRSA) are a global health burden dominated by which spread from hospitals causing a significant disease burden in a small number of bacterial clones. The pandemic EMRSA-16 clone the community and was characterized by resistance to penicillin and (ST36-II) has been widespread in UK hospitals for 20 y, but its evolu- production of the Panton-Valentine leukocidin (PVL) toxin (6–9). tionary origin and the molecular basis for its hospital association are The Southwest Pacific clone (SWP) is a contemporary PVL+ unclear. We carried out a Bayesian phylogenetic reconstruction on the community-associated MRSA clone, which has spread to several basis of the genome sequences of 87 S. aureus isolates including 60 continents and which largely causes skin and soft tissue infections of EMRSA-16 and 27 additional clonal complex 30 (CC30) isolates, collected from patients in three continents over a 53-y period. The otherwise healthy individuals (10, 11). In contrast to phage type 80/ three major pandemic clones to originate from the CC30 lineage, 81 and SWP, the EMRSA-16 (ST36) clone appears to be restricted including phage type 80/81, Southwest Pacific, and EMRSA-16, shared to the hospital setting and has reduced virulence due in part to low a most recent common ancestor that existed over 100 y ago, whereas levels of expression of cytolytic toxins (12). Along with the the hospital-associated EMRSA-16 clone is estimated to have emerged EMRSA-15 (ST22) clone, EMRSA-16 has been endemic in UK about 35 y ago. Our CC30 genome-wide analysis revealed striking hospitals for over 20 y and has also been reported less commonly in molecular correlates of hospital- or community-associated pandemics other European countries, Southeast Asia, South Africa, Australia, represented by mobile genetic elements and nonsynonymous and North America (3, 13–17). The high rate of MRSA infections mutations affecting antibiotic resistance and virulence. Importantly, and the rapid spread of HA-MRSA between UK hospitals led the phylogeographic analysis indicates that EMRSA-16 spread within the UK government to introduce stringent infection control legislation United Kingdom by transmission from hospitals in large population from 2003, resulting in a decrease in rates of nosocomial MRSA centers in London and Glasgow to regional health-care settings, implicating patient referrals as an important cause of nationwide infection (18, 19). Of note, EMRSA-16 prevalence has declined transmission. Taken together, the high-resolution phylogenomic more rapidly than that of EMRSA-15, implying the existence of approach used resulted in a unique understanding of the emergence unknown strain-dependent factors that confer increased suscepti- and transmission of a major MRSA clone and provided molecular bility to hospital infection prevention and control measures (18, 19). correlates of its hospital adaptation. Similar approaches for hospital- Despite its clinical importance, the evolution of the EMRSA-16 associated clones of other bacterial pathogens may inform appropri- clone, in addition to the molecular basis for its success are poorly ate measures for controlling their intra- and interhospital spread. understood. Here we use a phylogenomic approach to examine the diversity of EMRSA-16 relative to other CC30 pandemic clones. nosocomial | epidemiology The results represent a high resolution insight into the emergence, expansion, and transmission of a major clone of MRSA, revealing he Gram-positive bacterium Staphylococcus aureus is a unique molecular correlates for its hospital association. Tcomponent of the normal flora of about 30% of the human population, but is capable of causing severe infections of immu- nocompromised patients in hospitals and healthy humans in the Author contributions: P.R.M., K.E.T., G.F.E., A.R., D.A.R., and J.R.F. designed research; P.R.M., community (1). Hospital-associated methicillin-resistant S. aureus H.J.A.B., A.H., P.A.G., M.F., D.A.R., and J.R.F. performed research; M.T.G.H., E.J.F., D.M.A., (HA-MRSA) is represented by a small number of clones that rarely B.G.S., S.D.B., J.P., M.C.E., E.K.G., P.A.G., M.F., and A.M.K. contributed new reagents/analytic tools; P.R.M., K.E.T., G.F.E., M.T.G.H., E.J.F., M.C.E., A.R., D.A.R., and J.R.F. analyzed data; and cause disease outside of the health-care setting and that are char- P.R.M. and J.R.F. wrote the paper. β acterized by resistance to -lactam antibiotics in addition to other The authors declare no conflict of interest. front-line antimicrobials (2). During the last 60 y, the S. aureus This article is a PNAS Direct Submission. clonal complex 30 (CC30) has had a profound impact on global Data deposition: The sequences reported in this paper have been deposited in the human health by giving rise to three pandemic waves and the toxic National Center for Biotechnology Information (NCBI) sequence read archive database shock syndrome (TSS) epidemic (3, 4). Furthermore, one study (accession nos. SRA051389, ERA050956, and SRP000757). indicated S. aureus isolates from life-threatening endocarditis 1To whom correspondence should be addressed. E-mail: ross.fi[email protected]. infections are more likely to belong to CC30 than to other S. aureus This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. MICROBIOLOGY lineages (5). The first CC30 pandemic was caused by the 1073/pnas.1202869109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1202869109 PNAS | June 5, 2012 | vol. 109 | no. 23 | 9107–9112 Downloaded by guest on October 1, 2021 Results and Discussion as 1936 (95% HPDs, 1926–1945), the date for the MRCA of the Phylogenetic and Dating Analysis of CC30 Pandemics. The core ge- SWP clone was estimated as 1967 (95% HPDs, 1952–1984), and nome of the 87 CC30 isolates examined consisted of 2,381,276 the date for the MRCA of the EMRSA-16 clone was estimated as bases (82% of the MRSA252 reference genome), containing 1975 (95% HPDs, 1965–1983). The latter date precedes the first a total of 4,499 high-confidence single nucleotide polymorphisms reports of EMRSA-16 identification in UK hospitals by about 18 y. (SNPs). We applied a Bayesian coalescent method using a relaxed Finally, the date for the MRCA of the entire CC30 lineage was molecular clock model to infer the phylogeny and the rate of estimated as 1842 (95% HPDs, 1765–1909). molecular evolution of the CC30 lineage and its major clades. The Previously, Robinson et al. used multilocus sequence typing phylogeny indicates the existence of three major clades within the (MLST) and PCR genotyping to examine the evolution of CC30 CC30 lineage, representative of the major pandemic clones, 80/81, pandemic clones and inferred that the SWP clone originated SWP, and EMRSA-16, in addition to an EMRSA-16 sister clade from the historic phage type 80/81 clone (3). However, an im- represented by other epidemic CC30 isolates (Fig. 1). There was portant recent study by DeLeo et al. based on a comparative strong posterior support for the majority of nodes in the tree and genome sequence analysis of nine CC30 isolates demonstrated parsimony analysis indicates a very low frequency of homoplasies that the SWP clone is not a direct descendent of the phage 80/81 across the phylogenetic tree (consistency index of 0.92 for parsi- clone, but that each clone has evolved from a single ancestral mony informative sites), suggesting there was limited conflicting strain, which gave rise to all three CC30 pandemics (12). In phylogenetic signal. The mean nucleotide substitution rate within agreement with this finding, our phylogenetic analysis clearly − CC30 was 1.42 × 10 6 substitutions per site per year [95% highest demonstrates the independent origins of each of the three major − − posterior densities (HPDs) 1.04 × 10 6–1.80 × 10 6], which varied CC30 pandemic clones. Furthermore, the larger number of ge- negligibly depending on the clock model and choice of tree prior nome sequences included in the current study facilitated the use and within each pandemic clade.
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