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Edinburgh Research Explorer Edinburgh Research Explorer A genomic portrait of the emergence, evolution, and global spread of a methicillin resistant Staphylococcus aureus pandemic Citation for published version: Holden, MTG, Hsu, L-Y, Kurt, K, Weinert, LA, Mather, AE, Harris, SR, Strommenger, B, Layer, F, Witte, W, de Lencastre, H, Skov, R, Westh, H, Zemlickova, H, Coombs, G, Kearns, AM, Hill, RLR, Edgeworth, J, Gould, I, Gant, V, Cooke, J, Edwards, GF, McAdam, P, Templeton, KE, McCann, A, Zhou, Z, Castillo- Ramirez, S, Feil, EJ, Hudson, LO, Enright, MC, Balloux, F, Aanensen, DM, Spratt, BG, Fitzgerald, JR, Parkhill, J, Achtman, M, Bentley, SD & Nübel, U 2013, 'A genomic portrait of the emergence, evolution, and global spread of a methicillin resistant Staphylococcus aureus pandemic', Genome Research, vol. 23, no. 4, pp. 653-664. https://doi.org/10.1101/gr.147710.112 Digital Object Identifier (DOI): 10.1101/gr.147710.112 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Genome Research Publisher Rights Statement: This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full- issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/ General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 Research A genomic portrait of the emergence, evolution, and global spread of a methicillin-resistant Staphylococcus aureus pandemic Matthew T.G. Holden,1,25 Li-Yang Hsu,1,2 Kevin Kurt,3 Lucy A. Weinert,4,22 Alison E. Mather,1 Simon R. Harris,1 Birgit Strommenger,3 Franziska Layer,3 Wolfgang Witte,3 Herminia de Lencastre,5,6 Robert Skov,7 Henrik Westh,8,9 Helena Zˇemlicˇkova´,10 Geoffrey Coombs,11 Angela M. Kearns,12 Robert L.R. Hill,12 Jonathan Edgeworth,13 Ian Gould,14 Vanya Gant,15 Jonathan Cooke,16 Giles F. Edwards,17 Paul R. McAdam,18 Kate E. Templeton,19 Angela McCann,20 Zhemin Zhou,20 Santiago Castillo-Ramı´rez,21 Edward J. Feil,21 Lyndsey O. Hudson,4 Mark C. Enright,4,23 Francois Balloux,4,24 David M. Aanensen,4 Brian G. Spratt,4 J. Ross Fitzgerald,18 Julian Parkhill,1 Mark Achtman,20,25 Stephen D. Bentley,1 and Ulrich Nu¨bel3,25 1–21[Author affiliations appear at the end of the paper.] The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug- resistant bacteria that are adapted to thrive in hospitalized patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with health care. The most rapidly spreading and tenacious health-care-associated clone in Europe currently is EMRSA-15, which was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. Using phylogenomic methods to analyze the genome sequences for 193 S. aureus isolates, we were able to show that the current pandemic population of EMRSA-15 descends from a health-care-associated MRSA epidemic that spread throughout England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 subclone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this subclone over the last 20 yr has grown four times faster than its progenitor. Using comparative genomic analysis we identified the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome se- quencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens. [Supplemental material is available for this article.] Methicillin-resistant Staphylococcus aureus (MRSA) remains a ma- several times by acquiring variants of staphylococcal cassette jor global cause of health-care-associated infections since it was chromosome mec (SCCmec) elements that carry the mecA methi- first described five decades ago following the introduction of cillin resistance determinant (Robinson and Enright 2003; Nu¨bel penicillinase-stable b-lactam antibiotics into clinical practice et al. 2008). However, the vast majority of MRSA isolated world- (Klein et al. 2007). During this period, MRSA strains have emerged wide belong to a limited number of clones, some of which are as- sociated with global epidemics. Epidemic MRSA-15 (EMRSA-15) has proven to be particularly Present addresses: 22University of Cambridge, Cambridge CB2 1TN, United Kingdom; 23University of Bath, Bath BA2 7AY, United King- successful over the last two decades, transmitting rapidly within dom; 24University College London, Greater London WC1E 6BT, United and between hospitals, as well as to different countries. EMRSA- Kingdom. 15 carries a type IV SCCmec element and belongs to multilocus 25Corresponding authors E-mail [email protected] sequence type ST22. Initially isolated in the southeast of England E-mail [email protected] in 1991 (Richardson and Reith 1993), the spread of EMRSA-15 in the E-mail [email protected] UK health-care setting was rapid; by 2000, EMRSA-15 accounted Article published online before print. Article, supplemental material, and pub- lication date are at http://www.genome.org/cgi/doi/10.1101/gr.147710.112. for over 60% of MRSA nosocomial bacteremias in England Freely available online through the Genome Research Open Access option. (Johnson et al. 2001). Over this period the proportion of MRSA 23:653–664 Ó 2013, Published by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/13; www.genome.org Genome Research 653 www.genome.org Holden et al. among S. aureus bacteremia in the UK increased from <2% to 40% area, the spatiotemporal dynamics of the population structure and (Johnson et al. 2001). epidemic spread remain poorly understood, partially due to the Shortly after EMRSA-15 was reported in England, MRSA in- limited resolution provided by contemporary genotyping tools. distinguishable from EMRSA-15 were reported to cause outbreaks In this study we have investigated the origins and evolution of in other geographic regions, including Germany, the Czech Re- EMRSA-15 by whole-genome sequencing 193 ST22 isolates from public, Portugal, New Zealand, Australia, and Singapore (Pearman 15 countries, collected between 1990 and 2009. Integrating evo- et al. 2001; Witte et al. 2001; Hsu et al. 2005; Melter et al. 2006; lutionary and spatial information, we have reconstructed the spa- Amorim et al. 2007; Grundmann et al. 2010). These belong to tial and temporal dynamics underpinning the expansion of this multilocus sequence type ST22 or its close relatives. In a recent clone and ascertained the genetic changes correlating with its en- structured survey, ST22 was the most frequently found MRSA hanced spreading success. across Europe (Grundmann et al. 2010), and it was among the three most frequent MRSA clones in seven out of 15 countries for which quantitative data were available (Grundmann et al. 2010). Results Although reported in many countries, ST22-MRSA accounted Phylogenomic reconstruction of the ST22 lineage for only 0.2% of MRSA in a surveillance study recently performed in the USA (Limbago et al. 2009) and has not, as yet, been re- We determined full-genome sequences from 193 ST22 isolates ported from South America (Sola et al. 2008) and from large (Supplemental Table S1) including isolates both from hospital and parts of Asia (Arakere et al. 2005; Ko et al. 2005). ST22-MRSA has community settings, and also 12 isolates from the earliest de- repeatedly demonstrated its ability to supplant and replace other scription of EMRSA-15 (Richardson and Reith 1993). Once mobile formerly established MRSA strains (Hsu et al. 2005; Amorim genetic elements (MGEs) were excluded, a total of 8095 single et al. 2007; Aires-de-Sousa et al. 2008; Witte et al. 2008). Of fur- nucleotide polymorphisms (SNPs) in the ‘‘core’’ genome were used ther concern, ST22-MRSA containing the lukS/ F genes (encoding to reconstruct the evolutionary history of S. aureus ST22 (Fig. 1). the Panton-Valentine leucocidin) has been reported to cause These data revealed that the core genome has accumulated varia- community-associated infections (Linde et al. 2005; Witte et al. tion at a rate of 1.3 3 10À6 substitutions per nucleotide site per year 2007). (95% Bayesian credible intervals, 1.2 3 10À6 to 1.4 3 10À6; Sup- The mechanisms that lead to the emergence and spread of plemental Table S2). Substitution rates varied slightly among dif- MRSA strains are of great interest. Despite intense research in this ferent phylogenetic clades within ST22, but these differences Figure 1. Phylogeny of ST22 and the emergence of MRSA clones. (A) Maximum likelihood phylogenetic tree of ST22 isolates. The tree was rooted by using the distantly related S.
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