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Most Virulent Enterohemorrhagic E. coli on the Rise, Phylogenetics Suggests

NEW YORK (GenomeWeb News) – A particularly severe form of human infection is being linked to a subset of Escherichia coli O157:H7 strains, based on a new phylogenetic analysis of the bug.

In the study, published online last night in the Proceedings of the National Academy of Sciences, researchers at Michigan State University and elsewhere used phylogenetics to organize several hundred clinically relevant E. coli O157 strains into nine clades. As it turned out, many of the strains isolated from people with the most serious E. coli O157-related disease clustered in just one of these clades: clade eight, which seems to be more prevalent in recent years.

“There certainly is a difference,” senior author Thomas Whittam, a microbial evolutionary biologist at Michigan State University, told GenomeWeb Daily News. “It’s clear that a high rate of hospitalization was concentrated … in clade eight.”

E. coli naturally inhabits the gut of all animals, humans included. It’s normally benign or even helpful, warding off some dangerous bacteria and producing useful vitamins. But a sub-population of E. coli, called O157:H7 or enterohemorrhagic E. coli, synthesizes so-called Shiga toxins that can cause serious human disease.

First recognized in the early 1980s, EHEC outbreaks have been linked to a variety of food sources including undercooked ground beef, alfalfa, spinach, unpasteurized fruit juice, salami, wild game meat, and raw milk.

The bacteria’s toxins can cause hemorrhagic colitis, which is characterized by abdominal pain, bloody diarrhea, and sometimes vomiting. Young children and the elderly are often hit hardest by the bug. In some cases, infected individuals develop hemolytic uremic syndrome, which can result in kidney failure, seizures, strokes, and other serious complications.

The severity of EHEC outbreak varies wildly, though. For instance, during a particularly powerful North American outbreak in 2006, more than half of those infected after eating tainted spinach had to be hospitalized. More than ten percent developed hemolytic uremic syndrome. In contrast, a large outbreak in Japan a decade earlier had low rates of both hospitalization and HUS.

This led Whittam and his colleagues to speculate that E. coli O157 may have evolved to become more virulent, perhaps via different Shiga toxin gene variants.

To assess the bacteria’s clinical diversity, the team genotyped 528 EHEC O157 strains isolated from infected patients in Michigan and elsewhere, evaluating 96 SNPs in 83 genes. To do this, they used comparative genome sequencing microarrays, multilocus sequence typing, virulence gene sequencing, and in silico comparisons. They also used real-time PCR to pin down synonymous and nonsynonymous SNPs.

When they focused in on 39 distinct SNP genotypes and used these to create a phylogenetic network, the team found that the EHEC strains tested fell into nine different clades. Interestingly, there were not only differences in toxin genes between clades, but also in the severity of human infection associated with different clades.

In particular, strains belonging to clade eight, which consistently contains five distinct SNP genotypes, were most often associated with severe disease. As it turned out, individuals infected with EHEC from clade eight also tended to be younger — frequently under eighteen — and more likely to develop HUS.  

The researchers also sequenced the 2006 North American spinach outbreak strain — which also belongs to clade eight — using a Roche/454 Life Sciences’ GS 20 instrument. As it turned out, the spinach strain had, indeed, diverged quite dramatically from earlier strains such as the Japanese outbreak strain.

Over the past five years or so, Whittam noted, there also seem to be changes in different clades’ prevalence, with clade eight infections apparently increasing and some others decreasing. Still, it’s unclear why clade eight infections are more prevalent — especially in Michigan — in recent years. Whittam speculated that this could be related to the food source that carries the bug, the amount of toxin those strains produce, or some other yet unknown factor.

Eventually, he said, they hope to discover what makes certain EHEC clades so dangerous so that they can better predict and curb EHEC outbreaks. Whittam and his team are currently working on developing a rapid SNP analysis test to quickly identify E. coli O147 strains that may be particularly useful for rapid, vegetable-related outbreaks.  

And while this study was primarily focused on clinically relevant E. coli O157 strains, Whittam said it would be useful to expand the sources tested to include animal and vegetable-related strains not yet implicated in human disease since it seems just a subset of E. coli O157 strains have infected humans so far.

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