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Scientists Identify New Killer Transplant Virus Using 454 Sequencing Platform

NEW YORK (GenomeWeb News) – American and Australian scientists reported today that they have used high-throughput DNA sequencing and bioinformatics to identify the virus behind the deaths of three Australian transplant recipients.
The three women died from a mysterious virus last April after receiving organs from the same donor. Now, researchers from Columbia University’s Mailman School of Public Health, the US Centers for Disease Control and Prevention, the Victorian Infectious Diseases Reference Laboratory in Melbourne, and Roche’s 454 Life Sciences have fingered the culprit: a novel arenavirus. Their findings appeared online today in the New England Journal of Medicine.
“We would not have found it at all but for the high-throughput sequencing,” senior author Ian Lipkin, an epidemiologist at Columbia University, told GenomeWeb Daily News. “I think [the high-throughput approach] really will change the way things are done.”
The three patients — who all received organs from the same donor on the same day — developed febrile illness, seizures brought on by fever, about a month after their transplants. Despite several attempts to identify the virus causing this infection, using everything from traditional culturing techniques to PCR and microarrays, scientists at the infectious disease lab in Melbourne had no suspects. They contacted Lipkin, who led the new, high-tech virus hunt.
Using RNA from liver and kidney tissues from two of the deceased transplant recipients, Lipkin and his team applied 454 Life Sciences’ rapid sequencing technology combined with bioinformatics algorithms developed at Columbia to amplify thousands of sequences, subtract human and primer sequences from the mix, and cluster suspicious sequences.
This helped them narrow down their search from the 103,632 sequences they had started with to just 14 arenavirus sequences. Their subsequent work, including tissue culture studies, electron microscopy, and immunohistochemical and serological tests, confirmed the identity of the new arenavirus as well as its specificity and pathogenicity.
In the past, a similar arenavirus — called the lymphocytic choriomeningitis virus — has transmitted infections during organ transplants. But the new Australian virus didn’t resemble that LCMV strain closely enough to be detected by typical screening techniques and appeared to be unique.
While it is not uncommon to use sequencing to identify unknown pathogens, this appears to be the first report describing the use of high-throughput pyrosequencing techniques in a public health arena to identify a human pathogen. In an editorial also appearing in today’s issue of NEJM, University of Alabama at Birmingham pediatrician and microbiologist Richard Whitley praised the method’s potential for identifying other infectious agents in the future.
“[T]his application of new diagnostic techniques may ultimately transform microbiologic testing,” Whitley wrote. “As contemporary molecular diagnostic approaches are applied to medical conditions with potentially infectious causes, metagenomic pyrosequencing should permit us to expand our list of offending pathogens.”
“This is another example for the potential of the 454 sequencing technology in various application arenas,” Manfred Baier, head of Roche Applied Science, said in a statement. “The identification of the virus is an important first step in further enhancing the safety of transplantations.”