title: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: mtg@ssi.dk.
authors.forename: Marc
authors.initials: M
authors.lastname: Stegger
authors.forename: Thierry
authors.initials: T
authors.lastname: Wirth
authors.forename: Paal S
authors.initials: PS
authors.lastname: Andersen
authors.affiliation: Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Skov
authors.affiliation: Département Systématique et Evolution, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: De Grassi
authors.forename: Patricia Martins
authors.initials: PM
authors.lastname: Simões
authors.forename: Anne
authors.initials: A
authors.lastname: Tristan
authors.affiliation: Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Petersen
authors.forename: Maliha
authors.initials: M
authors.lastname: Aziz
authors.affiliation: Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Kiil
authors.affiliation: Institute of Microbiology and Immunology, Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Cirković
authors.affiliation: Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
authors.forename: Edet E
authors.initials: EE
authors.lastname: Udo
authors.affiliation: Servicio de Microbiología, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: del Campo
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Vuopio-Varkila
authors.affiliation: Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Norazah
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Genomics and Proteomics Research Laboratory, Department of Biology, Lebanese American University, Byblos, Lebanon.
authors.forename: Sima
authors.initials: S
authors.lastname: Tokajian
authors.affiliation: Institute of Medical Microbiology, University Hospital Münster, Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Peters
authors.affiliation: Institute of Medical Microbiology, University Hospital Münster, Münster, Germany.
authors.forename: Frieder
authors.initials: F
authors.lastname: Schaumburg
authors.affiliation: Swedish Institute for Infectious Disease Control, Solna, Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Olsson-Liljequist
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
authors.affiliation: Pathogen Genomics Division, Translational Genomics Research Institute, Flagstaff, Arizona, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Driebe
authors.affiliation: Department of Anthropology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik E
authors.initials: HE
authors.lastname: Vigh
authors.affiliation: Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Adebayo
authors.initials: A
authors.lastname: Shittu
authors.affiliation: Department of Bacteriology, Centre Hispitalo-universitaire Mustapha-Pacha, Algiers, Algeria.
authors.forename: Nadjia
authors.initials: N
authors.lastname: Ramdani-Bougessa
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rasigade
authors.forename: Lance B
authors.initials: LB
authors.lastname: Price
authors.forename: Francois
authors.initials: F
authors.lastname: Vandenesch
authors.affiliation: Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Anders R
authors.initials: AR
authors.lastname: Larsen
authors.forename: Frederic
authors.initials: F
authors.lastname: Laurent
mesh_terms: D000352:Africa, Northern; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics; D015373:Bacterial Typing Techniques; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial; D005060:Europe; D019143:Evolution, Molecular; D005098:Exotoxins / Q000235:genetics; D005798:Genes, Bacterial; D007956:Leukocidins / Q000235:genetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D008877:Middle East; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D058974:Phylogeography; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004269:DNA, Bacterial; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus