The precise origin of the virus that causes the deadly Middle East respiratory syndrome (MERS) remains obscure. But the largest genetic analysis to date reveals that several varieties of the MERS virus are circulating in Saudi Arabia, leading some to believe the virus reached humans from multiple sources.
Since the first documented cases in 2012, MERS has killed 58 people and sickened 132, most of them in Saudi Arabia, according to the U.S. Centers for Disease Control and Prevention. Scientists know the virus has a limited ability to spread from person to person, but they aren’t sure about the path it took to reach its first human victims. Last month, a small fragment of the virus’s genome turned up in a Saudi Arabian bat, and retired racing camels in Oman were found to carry antibodies against the virus. However, a direct link between these possible animal hosts, known as reservoirs, and the first people who contracted MERS hasn’t been found.
To explore the genetic diversity of MERS, virologist Paul Kellam of the Wellcome Trust Sanger Institute in Hinxton, United Kingdom, and an international team of colleagues sequenced viral genomes sampled from 21 patients in Saudi Arabia between June 2012 and June 2013. Many came from an outbreak of the virus at a hospital in the eastern city of Al-Hasa this spring. The group hoped to capitalize on the differences that emerge as a virus evolves to work backwards to the earliest MERS ancestors. Using these differences, the group constructed a tree of the 21 cases to predict how long ago the virus may have appeared in humans, how much it has changed since then, and how it has spread geographically.
The analysis, published online this week in The Lancet, revealed significant variety among the viral genomes drawn from the different patients. Based on the large amount of variation, the authors estimate that at least three distinct versions of the virus exist in the Saudi Arabian population. Even samples collected within a few days of each other during the Al-Hasa outbreak had very different genomes. Since the virus couldn’t have evolved these changes in such a short time, Kellam says, there are two possible explanations. One is that MERS could be infecting many more people than are actually getting sick, evolving all the time. But with no evidence of a large asymptomatic population so far, Kellam and his colleagues favor a second scenario: MERS evolved and diversified in animals and then infected humans on multiple occasions. As for its nonhuman source, Kellam says: “It’s conjecture until there’s evidence of what the reservoir is.” But the possibility that the introduction of MERS is ongoing “changes the way you can think about infection control.” If scientists continue to see new genetic varieties not consistent with human-to-human transmission, it’s crucial to identify that animal source and limit its contact with humans, he says.
The data suggest that MERS—which belongs to a deadly family known as coronaviruses—first emerged in humans around July of 2011. But Kellam cautions that because the data set is small, this finding is preliminary.
The publication is welcome news to other researchers working with MERS. “It’s data that everyone that’s studying these coronaviruses has been waiting on,” says Matthew Frieman, a microbiologist at the University of Maryland in Baltimore who is developing a potential vaccine for the virus. He agrees that it’s unlikely MERS mutated dramatically while moving from person to person. Multiple lineages could mean the virus is still mutating and could develop a more harmful form. So far, it has not been as lethal as some other coronaviruses, such as SARS.
Columbia University virologist Ian Lipkin praises the Wellcome group’s work for combining the genetic analysis with “classical gumshoe epidemiology,” but isn’t convinced by the authors’ bottom line. At this point, we can’t rule out the “asymptomatic humans” hypothesis either, he says.
Others have broader concerns. Virologist Christian Drosten of the University of Bonn in Germany calls the group’s conclusions “a very clear, but also a bold message.” He worries that the genetic sequence Kellam and colleagues published for the earliest patient on the tree is radically different from a previous sequence for the same patient, and may have thrown off the estimates of the virus’s evolutionary rate. Drosten says sequencing genomes from other samples, including crucial cases outside of Saudi Arabia, will tell a more complete MERS story.