Origin and evolution of European community-acquired methicillin-resistant Staphylococcus aureus

Abstract

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations.

Importance: With increasing levels of CA-MRSA reported from most parts of the Western world, there is a great interest in understanding the origin and factors associated with the emergence of these epidemic lineages. To trace the origin, evolution, and dissemination pattern of the European CA-MRSA clone (CC80), we sequenced a global collection of strains of the S. aureus CC80 lineage. Our study determined that a single descendant of a PVL-positive methicillin-sensitive ancestor circulating in sub-Saharan Africa rose to become the dominant CA-MRSA clone in Europe, the Middle East, and North Africa. In the transition from a methicillin-susceptible lineage to a successful CA-MRSA clone, it simultaneously became resistant to fusidic acid, a widely used antibiotic for skin and soft tissue infections, thus demonstrating the importance of antibiotic selection in the success of this clone. This finding furthermore highlights the significance of horizontal gene acquisitions and underscores the combined importance of these factors for the success of CA-MRSA.

FIG 1

Rooted maximum-likelihood phylogeny of 97 CC80 isolates based on 3,493 SNPs, including 739 parsimony-informative SNPs. Strains are labeled with isolate number, isolate ID, country of origin, and year of sampling. Countries of origin: alg, Algeria; fa, France; swi, Switzerland; bel, Belgium; jo, Jordan: den, Denmark; swe, Sweden; mal, Malaysia; kuw, Kuwait; spa, Spain; ge, Germany; gr, Greece; fin, Finland; om, Romania; se, Serbia; slo, Slovenia; pol, Poland; tun, Tunesia; tog; Toga; nig, Nigeria; uga, Uganda; gab, Gabon. Columns 1 to 3 show the presence of the methicillin resistance determinant mecA, the fusidic acid resistance determinant fusB, and the tetracycline resistance determinant tet(K). The presence and absence of genetic elements are indicated by black and white, respectively. Gray bars in the SCCmec column indicate remnants of SCC in MSSA isolates, and hatched bars in the tet(K) column denote the pT181 and pT45 plasmids.

FIG 2

Bayesian analyses of the CC80 complex. (A) DensiTree representation of the Bayesian coalescent trees using a strict clock model based on 3,493 SNPs. Tips of the trees are constrained by year of isolation; the time scale is shown at the top. (B) Posterior estimates of the TMRCA for the derived and sub-Saharan African strains under the strict clock model. (C) Effective population size through time (Bayesian skyline) of the S. aureus CC80 lineage. The shaded area represents the 95% confidence intervals, and the arrows point to potential socioeconomic events that might have impacted the demography of the MRSA population.