Origin, evolution, and global transmission of community-acquired Staphylococcus aureus ST8

Abstract

USA300 is a pandemic clonal lineage of hypervirulent, community-acquired, methicillin-resistant Staphylococcus aureus (CA-MRSA) with specific molecular characteristics. Despite its high clinical relevance, the evolutionary origin of USA300 remained unclear. We used comparative genomics of 224 temporal and spatial diverse S. aureus isolates of multilocus sequence type (ST) 8 to reconstruct the molecular evolution and global dissemination of ST8, including USA300. Analyses of core SNP diversity and accessory genome variations showed that the ancestor of all ST8 S. aureus most likely emerged in Central Europe in the mid-19th century. From here, ST8 was exported to North America in the early 20th century and progressively acquired the USA300 characteristics Panton-Valentine leukocidin (PVL), SCCmec IVa, the arginine catabolic mobile element (ACME), and a specific mutation in capsular polysaccharide gene cap5E Although the PVL-encoding phage ϕSa2USA was introduced into the ST8 background only once, various SCCmec types were introduced to ST8 at different times and places. Starting from North America, USA300 spread globally, including Africa. African USA300 isolates have aberrant spa-types (t112, t121) and form a monophyletic group within the clade of North American USA300. Large parts of ST8 methicillin-susceptible S. aureus (MSSA) isolated in Africa represent a symplesiomorphic group of ST8 (i.e., a group representing the characteristics of the ancestor), which are rarely found in other world regions. Isolates previously discussed as USA300 ancestors, including USA500 and a "historic" CA-MRSA from Western Australia, were shown to be only distantly related to recent USA300 clones.

Keywords: Africa; CA-MRSA; USA300; comparative genomics; molecular evolution.

Fig. 1.

Maximum-likelihood phylogeny of 224 ST8 S. aureus isolates based on 12,403 core genome single nucleotide polymorphisms. The colors represent the region of origin of each sample. Phylogenetic positions of the included NCBI RefSeq genomes (two USA300 and one USA500) are highlighted with asterisks. Information about the complete presence (black squares), partial presence (gray squares), or absence (white squares) of USA300-specific genetic features is given for each sample. Major genetic introduction events are indicated on the respective phylogenetic branches. (Scale bar: substitution per site.)

Fig. 2.

Bayesian maximum clade credibility tree calculated from 10,801 sampled trees. Branch colors represent the country of origin of each sample and their most recent common ancestor (MRCA), respectively. Major clade’s MRCA origins are verbalized using international country codes. Important groups like USA300 or the “Basal African” clade are highlighted with gray squares (annotation in bold). Time periods and age of clades can be inferred using the timeline at the bottom. The most recent isolate was collected in 2013; the MRCA of all isolates was dated to 1854 (HPD 95%, 1841 to 1865). MSSA, methicillin-susceptible S. aureus; PVL⁺, Panton–Valentine leukocidin positive; USA300-NAE, North American Epidemic USA300 clone; USA300-SAE, South American Epidemic USA300 clone. Detailed divergence timings and countries for each node are displayed in Fig. S1.

Fig. 3.

Phylogeographic evolution of S. aureus USA300. The figure shows a subset of the global transmission routes of different ST8 lineages, including USA300. Different lineages are highlighted in different colors; thick lines represent major transmission events during the evolution of USA300; dotted lines represent other transmissions. Transmission times are indicated on major routes. For a comprehensive view of all transmission routes, including single isolates, view Dataset S6 using Google Earth.