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

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 subSaharan 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. Received 11 April 2014 Accepted 16 July 2014 Published 26 August 2014 Citation Stegger M, Wirth T, Andersen PS, Skov RL, De Grassi A, Simões PM, Tristan A, Petersen A, Aziz M, Kiil K, Cirković I, Udo EE, del Campo R, Vuopio-Varkila J, Ahmad N, Tokajian S, Peters G, Schaumburg F, Olsson-Liljequist B, Givskov M, Driebe EE, Vigh HE, Shittu A, Ramdani-Bougessa N, Rasigade J, Price LB, Vandenesch F, Larsen AR, Laurent F. 2014. Origin and evolution of European community-acquired methicillin-resistant Staphylococcus aureus. mBio 5(5):e01044-14. doi:10.1128/mBio.01044-14. Editor Fernando Baquero, Ramón y Cajal University Hospital Copyright © 2014 Stegger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. Address correspondence to Marc Stegger, mtg@ssi.dk. RESEARCH ARTICLE crossmark September/October 2014 Volume 5 Issue 5 e01044-14 ® mbio.asm. org 1 m b.asm . rg on A uust 6, 2014 P ubished by m b.asm . rg D ow nladed fom A remarkable change was observed in the epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in the late 1990s with the emergence of new MRSA lineages causing infections in the community in otherwise healthy individuals with no reported contact with the health care system (1–4). Within a very few years, community-acquired MRSA (CA-MRSA) strains were observed worldwide, involving a number of different geographically distinct lineages, including the Southwest Pacific clone (sequence type 30 [ST30], associated with the staphylococcal cassette chromosome mec element [SCCmec] type IV [ST30-IV]) in East Asia and Oceania (5–8), USA400 (ST1-IV) and USA300 (ST8-IV) in the United States (9, 10), and the European CAMRSA clone (ST80-IV) in Europe, North Africa, and the Middle