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International Team Applies Comparative Genomics to Hospital Acquired Infection-Causing Bacteria

NEW YORK (GenomeWeb News) – An international research team used comparative genomics to look for the genetic causes of increased virulence in a strain of Clostridium difficile involved in hospital-acquired infections.

In a paper appearing online today in Genome Biology, a team of British, French, and American researchers compared three C. difficile strains: a non-epidemic strain with the so-called 012 ribotype, a non-virulent strain with the 027 ribotype, and a hyper-virulent 027 strain. In so doing, the team identified genetic markers that they say may be useful for understanding the nature of increased C. difficile virulence.

"Several studies have shown that patients infected with these [more virulent] PCR-ribotype 027 strains have more severe diarrhea, higher mortality and more recurrences," senior author Brendan Wren, a genetics, molecular biology, and pathology researcher at the London School of Hygiene and Tropical Medicine, and his colleagues wrote. "This study provides genetic markers for the identification of 027 strains and offers a unique opportunity to explain their emergence."

C. difficile are a type of anaerobic bacteria that live in the mammalian gut. Some strains can cause serious infections in humans, particularly in individuals with compromised immune systems. The infection can cause everything from diarrhea to a more severe condition called pseudo-membranous colitis. C. difficile also tends to infect individuals taking antibiotics, the researchers explained, likely by replacing harmless gut bacteria displaced by the antibiotic therapy.

Concerns about C. difficile are increasing, due to a spate of infections in North America and Europe over the past five years or so involving a virulent 027 strain. These outbreaks have been more severe — and linked to greater mortality — than outbreaks reported previously, the team noted. And because the bacteria can form spores that linger in the environment, C. difficile recurrence is a major concern.

Although several genetic and phylogenetic studies have been conducted in recent years, the genetic underpinnings of the recently emerging, virulent form of the 027 strain remain murky.

In an effort to explore this further, Wren and his team used a combination of Roche 454, ABI 3730, and Illumina technology to sequence the genomes of a non-epidemic 027 strain called CD196 and a hyper-virulent 027 strain called R20291. They then compared these to one another and to the genome of a non-virulent C. difficile strain from the 012 ribotype, which was sequenced by researchers at the Wellcome Trust Sanger Institute and elsewhere in 2006.

In general, the researchers found that all three C. difficile genomes were well conserved, sharing 3,247 core genes. And although two of the strains are considered much less virulent than the third, all three genomes shared genes involved in antimicrobial resistance, sporulation, and other key processes.

Even so, there were differences both between 027 and 012 ribotypes and between the virulent and non-virulent forms of the 027 strains. For instance, both 027 strains produce the same toxin type, which differs from that produced by 012. The 027 genomes also contain mutations that render them resistant to fluoroquinolone-based antibiotics.

In addition, the 027 genomes housed 234 genes not present in the genome of the 012 ribotype genome. And, the team noted, many of these genes belonged to pathways involved in processes such as motility, toxicity, and antibiotic resistance.

Meanwhile, the genome of the virulent, epidemic form of 027 contained five regions that were missing in both of the non-epidemic strains. Among them: transcriptional regulators, a phage island, and a two part regulatory system.

Based on their analyses, the researchers suspect that the virulent form of 027 C. difficile acquired at least some of these genes over the past 20 years or so — concurrent with their rise as pathogens in hospitals and elsewhere.

"The observed gene differences between these strains might individually or collectively explain why modern 027 strains are more likely to be epidemic and could explain the higher case-fatality ratio and persistence associated with infection by these strains," Wren and his co-authors wrote.

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