Staphylococcus aureus CC398: Host Adaptation and Emergence of Methicillin Resistance in Livestock
Authors: Price Lance B. , Stegger Marc , Hasman Henrik , Aziz Maliha , Larsen Jesper , Andersen Paal Skytt , Pearson Talima , Waters Andrew E. , Foster Jeffrey T. , Schupp James , Gillece John , Driebe Elizabeth , Liu Cindy M. , Springer Burkhard , Zdovc Irena , Battisti Antonio , Franco Alessia , Żmudzki Jacek , Schwarz Stefan , Butaye Patrick , Jouy Eric , Pomba Constanca , Porrero M. Concepción , Ruimy Raymond , Smith Tara C. , Robinson D. Ashley , Weese J. Scott , Arriola Carmen Sofia , Yu Fangyou , Laurent Frederic , Keim Paul , Skov Robert , Aarestrup Frank M. 
Published: February 2012

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 (SCC
mec
) 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 SCC
mec
subtypes is suggestive of strong and diverse antimicrobial selection associated with food animal production.

IMPORTANCE
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.