title: Staphylococcus aureus CC398: host adaptation and emergence of methicillin resistance in livestock.
abstract: Since its discovery in the early 2000s, methicillin-resistant Staphylococcus aureus (MRSA) clonal complex 398 (CC398) has become a rapidly emerging cause of human infections, most often associated with livestock exposure. We applied whole-genome sequence typing to characterize a diverse collection of CC398 isolates (n = 89), including MRSA and methicillin-susceptible S. aureus (MSSA) from animals and humans spanning 19 countries and four continents. We identified 4,238 single nucleotide polymorphisms (SNPs) among the 89 core genomes. Minimal homoplasy (consistency index = 0.9591) was detected among parsimony-informative SNPs, allowing for the generation of a highly accurate phylogenetic reconstruction of the CC398 clonal lineage. Phylogenetic analyses revealed that MSSA from humans formed the most ancestral clades. The most derived lineages were composed predominantly of livestock-associated MRSA possessing three different staphylococcal cassette chromosome mec element (SCCmec) types (IV, V, and VII-like) including nine subtypes. The human-associated isolates from the basal clades carried phages encoding human innate immune modulators that were largely missing among the livestock-associated isolates. Our results strongly suggest that livestock-associated MRSA CC398 originated in humans as MSSA. The lineage appears to have undergone a rapid radiation in conjunction with the jump from humans to livestock, where it subsequently acquired tetracycline and methicillin resistance. Further analyses are required to estimate the number of independent genetic events leading to the methicillin-resistant sublineages, but the diversity of SCCmec subtypes is suggestive of strong and diverse antimicrobial selection associated with food animal production.
  
  
  OBJECTIVE
  Modern food animal production is characterized by densely concentrated animals and routine antibiotic use, which may facilitate the emergence of novel antibiotic-resistant zoonotic pathogens. Our findings strongly support the idea that livestock-associated MRSA CC398 originated as MSSA in humans. The jump of CC398 from humans to livestock was accompanied by the loss of phage-carried human virulence genes, which likely attenuated its zoonotic potential, but it was also accompanied by the acquisition of tetracycline and methicillin resistance. Our findings exemplify a bidirectional zoonotic exchange and underscore the potential public health risks of widespread antibiotic use in food animal production.
authors.affiliation: Translational Genomics Research Institute (TGen), Pathogen Genomics Division, Flagstaff, Arizona, USA. lprice@tgen.org
authors.forename: Lance B
authors.initials: LB
authors.lastname: Price
authors.forename: Marc
authors.initials: M
authors.lastname: Stegger
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasman
authors.forename: Maliha
authors.initials: M
authors.lastname: Aziz
authors.forename: Jesper
authors.initials: J
authors.lastname: Larsen
authors.forename: Paal Skytt
authors.initials: PS
authors.lastname: Andersen
authors.forename: Talima
authors.initials: T
authors.lastname: Pearson
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Waters
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Foster
authors.forename: James
authors.initials: J
authors.lastname: Schupp
authors.forename: John
authors.initials: J
authors.lastname: Gillece
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Driebe
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Liu
authors.forename: Burkhard
authors.initials: B
authors.lastname: Springer
authors.forename: Irena
authors.initials: I
authors.lastname: Zdovc
authors.forename: Antonio
authors.initials: A
authors.lastname: Battisti
authors.forename: Alessia
authors.initials: A
authors.lastname: Franco
authors.forename: Jacek
authors.initials: J
authors.lastname: Zmudzki
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwarz
authors.forename: Patrick
authors.initials: P
authors.lastname: Butaye
authors.forename: Eric
authors.initials: E
authors.lastname: Jouy
authors.forename: Constanca
authors.initials: C
authors.lastname: Pomba
authors.forename: M Concepción
authors.initials: MC
authors.lastname: Porrero
authors.forename: Raymond
authors.initials: R
authors.lastname: Ruimy
authors.forename: Tara C
authors.initials: TC
authors.lastname: Smith
authors.forename: D Ashley
authors.initials: DA
authors.lastname: Robinson
authors.forename: J Scott
authors.initials: JS
authors.lastname: Weese
authors.forename: Carmen Sofia
authors.initials: CS
authors.lastname: Arriola
authors.forename: Fangyou
authors.initials: F
authors.lastname: Yu
authors.forename: Frederic
authors.initials: F
authors.lastname: Laurent
authors.forename: Paul
authors.initials: P
authors.lastname: Keim
authors.forename: Robert
authors.initials: R
authors.lastname: Skov
authors.forename: Frank M
authors.initials: FM
authors.lastname: Aarestrup
mesh_terms: D000220:Adaptation, Biological; D000818:Animals; D015373:Bacterial Typing Techniques; D001435:Bacteriophages / Q000235:genetics; D002876:Chromosomes, Bacterial / Q000235:genetics / Q000378:metabolism; D021821:Communicable Diseases, Emerging / Q000382:microbiology* / Q000635:transmission; D005516:Food Microbiology; D016680:Genome, Bacterial; D006801:Humans; D058751:Livestock / Q000382:microbiology*; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D013203:Staphylococcal Infections / Q000382:microbiology / Q000635:transmission; D013211:Staphylococcus aureus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D013752:Tetracycline / Q000494:pharmacology; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism; D015047:Zoonoses / Q000382:microbiology / Q000635:transmission
chemical_list: D037521:Virulence Factors; D013752:Tetracycline; D008712:Methicillin