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Phylogenetic Features Point to Human Source for Livestock MRSA Strain

NEW YORK (GenomeWeb News) – A methicillin-resistant Staphylococcus aureus, or MRSA, strain found in agricultural animals likely originated from an antibiotic-susceptible form of S. aureus found in humans that acquired the changes needed to resist antibiotics once it moved into livestock, according to a phylogenetic analysis published online today in mBio.

An international group led by investigators at the Translational Genomics Research Institute and the Technical University of Denmark surveyed the genetic patterns in 89 animal and human isolates of a livestock-associated S. aureus strain known as CC398. Phylogenetic analyses of isolates sequenced for the study suggest that the drug-resistant CC398 now found in pigs and other livestock stemmed from a methicillin-susceptible version of the bug that was passed from humans to animals.

The advent of antiobiotic resistance — first to tetracycline and then to methicillin — in CC398 appears to have been a consequence of selective pressure caused by excess antibiotic use in agriculture, researchers argued.

"Our findings underscore the potential public health risks of widespread antibiotic use in food animal production," first author Lance Price, director of TGen's Center for Food Microbiology and Environmental Health, said in a statement. "[Staphylococcus aureus] thrives in crowded and unsanitary conditions. Add antibiotics to that environment and you're going to create a public health problem."

MRSA strains found both in health care settings and in the community have been implicated in a range of skin infections that can become invasive and even life threatening, the study authors explained.

But the advent of a new, livestock-associated version of MRSA within clonal complex 398 (also known as CC398 or ST398) almost a decade ago left researchers scratching their heads over the origins of this strain, which turns up with some regularity in live animals and meat products.

Though the first human infections with CC398 were limited to those who regularly came in contact with livestock, the strain is increasingly being implicated in MRSA infections that occur more broadly, the team noted.

"Given its rapid emergence and trajectory of increasing importance in humans," they wrote, "the evolutionary history of MRSA CC398 has relevance for the epidemiology of MRSA and global health."

In an effort to retrace the emergence of CC398, researchers did whole-genome paired-end sequencing on 89 methicillin-susceptible or –resistant CC398 isolates collected from pigs, poultry, cows, horses, and humans in 19 countries using the Illumina GAIIx.

By comparing genome sequences from the isolates, researchers tracked down more than 4,200 SNPs in the CC398 isolates.

And their phylogenetic analyses of the whole-genome sequence typing data indicated that the ancestral form of CC398 was a methicillin-sensitive S. aureus strain found in humans. That strain seems to have been passed to livestock, they explained, where it evolved into sub-types with resistance to tetracycline and, eventually, methicillin.

Most of livestock-associated isolates seem to have lost some of the bacteria-infecting viruses or phages that contribute to virulence in humans, the study suggests. On the other hand, the more derived forms of CC398 that occur in livestock have acquired staphylococcal sequence cassettes containing at least three types of so-called mec elements.

Almost all of the livestock-associated isolated also contained a tetracycline resistance gene, explaining some of the drug resistance seen in CC398. Still, the study's authors noted that more work will be needed to get a handle on all of the genetic changes that help MRSA sub-types of the CC398 strain dodge tetracycline and methicillin.

Based on their findings so far, the team suspects that routine antibiotic use in agriculture may have selected for isolates capable of avoiding the drugs.

"Further analyses are required to estimate the number of independent genetic events leading to the methicillin-resistant sub-lineages," researchers wrote, "but the diversity of [staphylococcal cassette chromosome mec] sub-types is suggestive of strong and diverse antimicrobial selection associated with food animal production."

"The most powerful force in evolution is selection," co-author Paul Keim, director of pathogen genomics at TGen and of microbial genetics and genomics at Northern Arizona University, said in a statement. "[I]n this case, humans have supplied a strong force through the excessive use of antibiotic drugs in farm animal production."

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