When researchers committed to first mapping E. coli genomes back at the turn of the millennium, the sequencing process was a considerable technological undertaking, requiring millions of dollars, months of computational horsepower and further months of analysis after the number crunching. But when it comes to microbial genomics, the sequencing technology seems to evolve even faster than the subject matter.
On July 27, a team led by researchers at the University of Maryland School of Medicine Institute for Genome Sciences published a paper in the New England Journal of Medicine on the completed genome mapping of E. coli O104:H4, the strain at the center of May’s E. coli outbreak in Germany. For those without a calendar handy: The team published a peer-reviewed study of the genome less than three months from the outbreak’s inception.
As for the genome itself, it took the international collaborators a matter of days to complete their sequencing, making for an unprecedented turnaround in the amount of information available to healthcare providers and public health authorities while it could still prove critical to fighting the outbreak.
“I hope this will be looked back as a seminal event in using microbial genomics as a clinically relevant diagnostic tool,” said David Rasko, Ph.D., lead author of the paper and assistant professor of microbiology and immunology at the University of Maryland.
Following their rapid sequencing of O104’s genes, research teams around the globe — from the Beijing Genome Institute to the World Health Organization’s E. coli research center in Denmark — began openly sharing data online with each other and the public. The open collaboration led to what Rasko has described as the first “open source” analysis of a microbial genome.
Through their analysis, the collaborators discovered that O104 had evolved from a type of E. coli typically thought to be harmless — enteroaggregative E. coli — and had acquired Shiga toxin-producing DNA from more virulent strains known as enterohemorrhagic E. coli. Medical professional only screen for enterohemorrhagic strains, predominantly O157:H7.
While some researchers initially labeled O104 a “hybrid” strain, Rasko was quick to clarify that O104 is not a hybrid as much as it is a common strain that happened to acquire an especially virulent trait.
“Knowing that the Shiga toxin is encoded on a mobile phage, this was bound to happen at some point,” Rasko said. “This was just Mother Nature at work — an organism recombining traits. There’s nothing inherently nefarious about it.”
Rasko said he expects further genome mapping of other strains to reveal more enteroaggregative E. coli with traits similar to O104’s. An outbreak of Germany’s magnitude, however, isn’t exactly a common occurrence.
“My personal view is that this was a really bad occurrence of a new organism coming to fruition at an opportune time. Other strains of E. coli with similar traits have been seen in the past and haven’t caused such large outbreaks,” Rasko said. “I like to explain it by thinking of it as a card game, where the E. coli strains pick up cards with different virulence factors and opportunities. If they’re good cards, they keep them and they win the game. In this case, it was kind of a perfect storm of the right organism, the right opportunity and the right vehicle to spread.”
Rasko said the mapping project couldn’t better explain why O104 affected seemingly healthy adults more severely than children or the elderly, nor why it appeared to be so much more virulent than other enterohemorrhagic strains that induce hemolytic uremic syndrome (HUS) such as E. coli O157:H7. The German outbreak saw roughly one in four patients suffering from HUS, whereas HUS cases in most E. coli outbreaks fall closer to one in 10.
Rasko and many other researchers concur with the theory that prescribing antibiotics among early infection patients likely contributed to the high number of HUS cases. O104 and other Shiga toxin-producing strains release potentially lethal levels of toxin when the patient takes antibiotics, and since medical professionals could not have known to screen for O104 when patients arrived with the initial symptoms, they may have prescribed antibiotics after ruling out O157 as the cause.
As Rasko said, the significance of this genome mapping derives from its unparalleled speed and resulting application in fighting the outbreak: The technology is now fast enough for medical professionals to rely on genomics for detailed information about the pathogen at the center of an ongoing outbreak, and it appears that the technology will only get faster.
Next, Rasko’s team plans to develop the phylogeny of the strain, figuring out how it evolved to possess its particular inventory of traits. And today, the technology is on their side.
“Previously, it took months to do this sequencing,” he said. “Now we’re down to days. We sequenced 12 strains in our study in less than a week. Back in 2002 or 2003, 12 strains would have taken almost a year.”
The paper, Origins of the E. Coli Strain Causing an Outbreak of Hemolytic-Uremic Syndrome in Germany can be read online.
Image source: E. coli O104:H4 outbreak strain from the Robert Koch Institute.