Molecular tracing of the emergence, adaptation, and transmission of hospital-associated methicillin-resistant Staphylococcus aureus

Abstract

Hospital-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health burden dominated by a small number of bacterial clones. The pandemic EMRSA-16 clone (ST36-II) has been widespread in UK hospitals for 20 y, but its evolutionary origin and the molecular basis for its hospital association are unclear. We carried out a Bayesian phylogenetic reconstruction on the basis of the genome sequences of 87 S. aureus isolates including 60 EMRSA-16 and 27 additional clonal complex 30 (CC30) isolates, collected from patients in three continents over a 53-y period. The three major pandemic clones to originate from the CC30 lineage, including phage type 80/81, Southwest Pacific, and EMRSA-16, shared a most recent common ancestor that existed over 100 y ago, whereas the hospital-associated EMRSA-16 clone is estimated to have emerged about 35 y ago. Our CC30 genome-wide analysis revealed striking molecular correlates of hospital- or community-associated pandemics represented by mobile genetic elements and nonsynonymous mutations affecting antibiotic resistance and virulence. Importantly, phylogeographic analysis indicates that EMRSA-16 spread within the United Kingdom by transmission from hospitals in large population centers in London and Glasgow to regional health-care settings, implicating patient referrals as an important cause of nationwide transmission. Taken together, the high-resolution phylogenomic approach used resulted in a unique understanding of the emergence and transmission of a major MRSA clone and provided molecular correlates of its hospital adaptation. Similar approaches for hospital-associated clones of other bacterial pathogens may inform appropriate measures for controlling their intra- and interhospital spread.

Fig. 1.

The CC30 lineage is divided into multiple distinct clades characterized by the presence of different toxin and antibiotic resistance determinants. Bayesian phylogenetic reconstruction of the CC30 lineage using all sites in the core genome. Blue, green, red, and gray shading correspond to the 80/81, Southwest Pacific, EMRSA-16, and other epidemic CC30 clones, respectively. Presence of the pvl locus is denoted by shaded black circles, tst carriage by shaded blue circles, intact crtM gene by shaded yellow circles, and SCCmec type is indicated for methicillin-resistant isolates. Branch lengths are scaled according to time-scale bar. All nodes have posterior probability support >0.8 unless labeled with an asterisk. Tip (isolate no.) and node labels are shown in Fig. S4.

Fig. 2.

EMRSA-16 has been transmitted from hospitals in major population centers to regional centers. (A) Bayesian phylogenetic reconstruction of UK EMRSA-16 isolates. Terminal branches representing London and Glasgow isolates are colored in red and blue, respectively. Black branches depict isolates from other locations. Branches are scaled with time (years). Gray shading indicates examples of geographically restricted subclades a and b. (B) Map of the United Kingdom indicating regions represented in the phylogeographic analysis (colored). Isolates were grouped by geographic region: L, London; SEE, southeast England; SE, south England; CE, central England; NS, north Scotland; ES, east Scotland; WS, west Scotland), and mean distance between cities was calculated. Blue and red shaded regions represent Glasgow (G) and London (L), respectively.