Staphylococcus aureus CC398: Host Adaptation and Emergence of Methicillin Resistance in Livestock

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Since its discovery in the early 2000s, methicillin-resistant<jats:named-content content-type="genus-species">Staphylococcus aureus</jats:named-content>(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 (<jats:italic>n</jats:italic>= 89), including MRSA and methicillin-susceptible<jats:named-content content-type="genus-species">S. aureus</jats:named-content>(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<jats:italic>mec</jats:italic>element (SCC<jats:italic>mec</jats:italic>) 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<jats:italic>mec</jats:italic>subtypes is suggestive of strong and diverse antimicrobial selection associated with food animal production.</jats:p><jats:p><jats:bold>IMPORTANCE</jats:bold>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.</jats:p>

Antimicrobial Resistance of Staphylococcus aureus Strains Acquired by Pig Farmers from Pigs

“…The large variability of SCCmec found in MRSA CC398 (12,23) suggests multiple acquisition events. A detailed phylogenetic comparison of CC398 strains isolated from humans and animals supported strong and diverse antimicrobial selection (28). Humans could be the original host of CC398, which acquired resistance to methicillin after its introduction to livestock from humans.…”

Zinc Resistance within Swine-Associated Methicillin-Resistant Staphylococcus aureus Isolates in the United States Is Associated with Multilocus Sequence Type Lineage

“…Additionally, a prominent feature of livestock-associated MRSA (LA-MRSA) ST398 isolates from Europe and North America is the high prevalence (61 to 74%) of zinc resistance seen in swine-associated isolates (18)(19)(20), relative to isolates from veal calves (42%) or humans (48%) (19,21). Zinc resistance in these MRSA isolates has been attributed to colocalization of the czrC gene (conferring zinc and cadmium resistance) on the type V staphylococcal cassette chromosome mec (SCCmec) element, which contains the mecA gene (conferring methicillin resistance).…”

What Is the Origin of Livestock-Associated Methicillin-Resistant Staphylococcus aureus Clonal Complex 398 Isolates from Humans without Livestock Contact? An Epidemiological and Genetic Analysis

“…There are indications that methicillin-susceptible Staphylococcus aureus (MSSA) CC398 switched hosts in the past as a result of human-animal interactions (12,14) and that it adapted to animals by losing several mobile genetic elements (MGEs) while gaining other MGEs, including resistance to tetracyclines and methicillin, before being reintroduced in humans as MRSA (3,15).…”