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Genomic Study Uncovers Human Bloodstream Infection Adaptations in Historical Hospital Samples

NEW YORK (GenomeWeb) – A team led by investigators at Harvard Medical School, the Massachusetts Eye and Ear Infirmary, and the Broad Institute retrospectively identified genetic features contributing to antibiotic resistance in a set of Enterococcus faecalis enterococcal strains involved in a hospital outbreak more than 30 years ago.

"This work identifies pathways that allow enterococci to survive the transition from the human gut into the bloodstream, enabling them to cause severe bacteremia associated with high mortality," said senior and corresponding author Michael Gilmore, an ophthalmology, microbiology, and infectious disease researcher affiliated with Harvard, the Massachusetts Eye and Ear Infirmary, and the Broad, in a statement.

Gilmore and his colleagues used genome sequencing, comparative genomics, and functional analyses to retrospectively assess dozens of isolates collected during an outbreak of multi-drug resistant E. faecalis in a Wisconsin hospital in the 1980s, comparing them to E. faecalis strains not involved in the outbreak. Their findings, published online today in Science Translational Medicine, uncovered multiple mutations affecting a handful of the overlapping loci as E. faecalis became resistance to existing and new drugs.

"Functional studies showed that mutating these loci rendered E. faecalis better able to withstand antibiotic pressure and innate immune defenses in the human bloodstream," the authors reported. "We also observed a shift in mutation pattern that corresponded to the introduction of carbapenem antibiotics in 1987."

Although E. faecalis and other enterococcal bacteria are ubiquitous in animal guts, the team noted that these microbes have emerged as an opportunistic bloodstream pathogen in healthcare settings, typically passing from one patient to the next by fecal to oral transmission.

"Enterococcal bloodstream infections occur mainly in hospitalized patients and are usually caused by hospital-adapted lineages," the authors wrote, noting that "[m]ultidrug-resistant, hospital-adapted enterococcal strains are believed to be readily acquired into the antibiotic-destabilized gut microbial community by ingestion from contaminated objects and surfaces."

To explore the transition from innocuous to infectious forms of E. faecalis in one hospital setting, the researchers used Illumina, Pacific Biosciences, and/or Oxford Nanopore Technologies approaches to do whole-genome sequencing on 62 strains from a multi-drug resistant E. faecalis collected by the University of Wisconsin Hospital and Clinics' Clinical Microbiology Laboratory during an outbreak from 1984 to 1988, along with 27 non-outbreak strains collected before or during that time.

"[W]e focused on characterizing de novo adaptation within each new patient," the authors noted, though variants shared across strains "could be similarly explored in future studies to investigate their impact on transmission of drug-resistant enterococci in the hospital environment."

The team's analysis placed the outbreak strains within sequence type 6, and uncovered 285 outbreak strain variants, including 64 that turned up in two or more strains and 15 variants that appeared to become fixed in the bugs over the course of the outbreak.

Though the specific alterations involved often did not overlap, the team found multiple mutations centered on the cydABDC operon, as well as a strong signal of selection involving a transcriptional regulator called gntR. The gntR mutations identified appeared to influence glycosyl hydrolase expression and cell surface polysaccharide profiles in follow up RNA sequencing experiments on wild type and gntR mutant strains.

Those results were backed up by the researchers' follow-up functional assays, which suggested that strains with gntR mutations became more adept at dodging antibiotic and immune pressures in a mouse abscess infection model compared with their gntR wild-type counterparts.

"Our study shows how an enterococcal outbreak lineage emerged and evolved over an extended hospital outbreak and how outbreak strains appeared to have responded to host immune selection and changing antibiotic regimens," the authors concluded. "These findings highlight pathways that could be further leveraged in the future for control and management of nosocomial enterococcal infections."

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