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Sanger-Led Team Uses Sequencing To Track MRSA Evolution and Spread

NEW YORK (GenomeWeb News) – A Wellcome Trust Sanger Institute-led research team published a proof-of-principle study online in Science today describing the use of high-throughput sequencing to track the evolution and spread of methicillin-resistant Staphylococcus aureus, or MRSA.

The researchers focused on a multiply antibiotic-resistant strain of the bug called ST239, which is found around the world and causes the bulk of hospital acquired MRSA infections in several countries. By sequencing genomes of more than 60 isolates — 43 collected around the world over about 20 years and 20 collected in a single hospital over several months — the team discerned relationships between isolates from different locations, tracked its spread from one continent to the next, and gained a better understanding of its transmission within a health care facility.

Beyond the implications for tracking and controlling MRSA, those involved with the study say their sequencing approach should also be useful for studying other types of microbes from a range of different environments.

"The ability to interrogate and resolve bacterial populations is applicable to a range of infectious diseases, as well as microbial ecology," senior author Stephen Bentley, a Wellcome Trust Sanger Institute researcher, and his co-authors wrote.

S. aureus, which is often found on the skin and in the nose, is usually harmless. But in some individuals it can cause mild to life-threatening infections.

MRSA is a particular health concern because it can survive treatment with the antibiotic methicillin. The bug has gained a great deal of attention in health care facilities, where it can cause hospital-acquired infections in individuals with compromised immunity, though community-acquired infections are also a growing concern.

As such, researchers and public health officials are interested in exploring how MRSA strains evolve and spread. Researchers noted that sequence databases based on multi-locus sequence typing, or MLST, data have helped in tracking MRSA and other pathogenic bacteria in the past. But, they added, because MLST looks at just a handful of genes, that approach can't differentiate between closely related bugs.

To refine their view of MRSA genetics, Bentley and his colleagues used the Illumina Genome Analyzer to sequence multiple MRSA isolates simultaneously. By tagging each sample with a unique sequence tag and running a dozen samples on each of the instrument's eight sequencing lanes, the researchers explained, they can sequence as many as 96 samples at once. That provides data for comparing whole MRSA genomes and pinpointing subtle differences between them, including SNPs and small insertions and deletions.

"This is a significant advance in the scale of genome sequencing that's available," Bentley told reporters during a press briefing yesterday. He said that for the current study, bulk bacterial sequencing took between four and six weeks and cost around 200 GBP ($320) per isolate.

The team applied this approach to the MRSA sequence type 239, sequencing the strain from 43 samples collected around the world between 1982 and 2003. They also sequenced 20 ST239 samples collected in the Sappasithiprasong hospital in Thailand over the span of seven months.

"We wanted to test whether our method could successfully zoom in and out to allow us to track infection on a global scale — from continent-to-continent, and also on the smallest scale — from person-to-person," co-lead author Simon Harris, also with the Wellcome Trust Sanger Institute, said in a statement.

They then compared the sequences with a completely sequenced reference isolate to find SNPs in the genomes and assembled a phylogenetic tree based on more than 4,300 variable sites in the ST239 genome.

The results so far suggest ST239 isolates typically cluster by location, with European isolates being particularly diverse — consistent with a potential European origin for this MRSA sequence type.

Although inter-continental transmission of ST239 MRSA seems to be rare, Harris told reporters during the briefing, there are cases in which it has occurred over the past few decades. For instance, the researchers found that the isolates in Portuguese hospitals in the early 1990s came from a European source but were replaced by isolates more similar to Brazilian ST239 in the late 1990s.

The researchers also noted that ST239 appears to be mutating faster than previously recognized, with a new mutation appearing roughly once every six weeks. Such mutations frequently affect parts of the genome related to drug resistance.

When the team narrowed in on a single health care setting, the Thai hospital, they found even greater genetic diversity between ST239 isolates than detected from the global samples.

Even so, they did find five isolates that were the same at all but 14 SNPs. The isolates had been collected over the span of several weeks and came from patients in adjacent hospital blocks, the researchers explained, suggesting genome sequencing can help track down the course of infection outbreaks within hospitals.

By applying a similar approach to other health care settings, the sequencing approach is expected to help find MRSA transmission hotspots that require elevated infection control strategies, co-author Sharon Peacock, a researcher affiliated with the University of Cambridge and Bangkok's Mahidol University, told reporters yesterday. "This technology can now be applied to different settings around the world," she said.

The bulk bacterial sequencing method also is expected to have applications for other medical and ecological studies as well. For instance, Bentley noted that Sanger researchers are using this sort of high-throughput sequencing to study the bacteria that cause diseases such as pneumonia, diarrhea, and tuberculosis.

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