On 19 March, a private Learjet touched down at the Munich airport. Inside the flying ambulance was a 73-year-old man from Abu Dhabi suffering from severe pneumonia. His family hoped German physicians might save his life.
Getting to know you. Many scientists are studying the new coronavirus, named for the crownlike spikes on its surface.
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They couldn't. A week later, the patient died at the Schwabing Clinic in northern Munich; his body was returned to the United Arab Emirates the next day. By then lab tests had shown that he was infected with a new coronavirus—the 17th known case worldwide and the 11th fatal victim. German officials have not revealed the man's identity, although that didn't stop the German tabloid Bild from claiming that he was "a sheik" from a "ruling family."
Whoever he was, the man's final journey provided scientists another opportunity to learn something about a respiratory disease outbreak that is still surrounded by questions. As Science went to press this week, University of Bonn virologist Christian Drosten said he had already sequenced the genome of the virus and would soon publish a comparison with other known sequences that may shed some light on the pattern of spread of nCoV (for novel coronavirus), as the World Health Organization (WHO) has dubbed the pathogen.
Part of the problem is that the affected countries have released little information about the outbreak so far and appear reluctant to collaborate with foreign researchers eager to find out more (Science, 15 March, p. 1264). Saudi Arabia, for instance, has reported nine cases to WHO, but for some, there is no information about patient age, sex, place of residence, or circumstances surrounding the infection. "A lot of key epidemiological information is missing," says virologist Vincent Munster of the Rocky Mountain Laboratories in Hamilton, Montana, which is part of the National Institute of Allergy and Infectious Diseases.
Since the virus emerged, scientists have published genomes of four strains isolated from patients, developed diagnostic tests, and set out to develop animal models—with the first successful attempt published online this week by Munster's team in The New England Journal of Medicine (NEJM). In a paper published in the 14 March issue of Nature, a team led by Bart Haagmans of Erasmus MC in Rotterdam, the Netherlands, also identified the virus's receptor, a well-known protein called DPP4 that sits on the surface of cells deep inside the human lung.
So far, the virus appears to circulate primarily in the Arabian Peninsula. Beside the nine patients from Saudi Arabia, there were two from Qatar, and the first two confirmed cases are now known to have occurred almost a year ago during an outbreak in Jordan. (They weren't identified and reported until last fall.) Three U.K. residents were also infected—two fatally—in January and February, but the first one of those had traveled to Saudi Arabia and Pakistan before falling ill and presumably picked up the virus on the way. That two of his family members became infected suggests that the virus spreads from human to human—although apparently not very efficiently, because 135 of the patients' contacts weren't infected.
Munster's short paper published online in NEJM this week not only provides researchers with a way to test candidate drugs and vaccines, but also offers formal proof that nCoV—often called hCoV-EMC, a name given to it by Erasmus MC researchers who first sequenced it—is the cause of the human disease. For the study, Munster and his colleagues inoculated six rhesus macaques with the virus. They developed pneumonia within 24 hours, with symptoms such as fever, cough, and reduced appetite, and necropsy revealed bright red lesions throughout their lower respiratory tracts. (The team's pathologist called the severity of the disease—which varied from one animal to the next—"mild to moderate.") The researchers reisolated the virus from the sick animals, thus fulfilling Koch's postulates, the classic set of criteria used to prove that a pathogen causes a disease.
Haagmans's group at Erasmus MC has tried the same experiment in cynomolgus macaques, but in that species the virus replicated poorly and didn't cause disease symptoms at all. Haagmans presented those findings at a Rotterdam meeting on 14 March, but says he wants to better understand why the animals were unaffected before publishing the data. It could be something species-specific, he says, or perhaps the monkeys were too young; previous work by the same group showed that older monkeys were much more susceptible to the SARS virus, a pattern that jibed with the human outbreak. (Munster's rhesus monkeys were between 6 and 12 years old.)
But few labs have monkeys, and they're expensive to work with; it's "really critical" that researchers also develop a small-animal model of infection and disease, says Matthew Frieman, a coronavirus researcher at the University of Maryland School of Medicine in Baltimore. Although the SARS virus does replicate in mice, and a mouse-adapted version makes them sick as well, Frieman and others have been unable to infect mice with the new virus. Munster has tried in vain with hamsters, and Haagmans's attempt in ferrets has failed as well. "We seem to have little luck with small animals," Haagmans says.
There are other ways of gauging the pathogenic potential of the new virus. A group led by Kwok-Yung Yuen at the University of Hong Kong tested whether it could infect a total of 27 cell lines from humans and animals, as a guide to which tissues and organs the virus might infect in the real world. In a paper published online by theJournal of Infectious Diseases on 26 March, they reported that nCoV replicated in 16 of the cell lines, more than any other known coronavirus—including human lung, kidney, intestinal, and liver cells. That might help explain why known cases of the disease have been so severe, the authors said.
But other researchers balked at that. In an accompanying commentary, Kenneth McIntosh of Boston Children's Hospital cautioned that studies of human cell lines—including some derived from tumors—often have little power to predict what happens in patients. "I think they drew too many conclusions," Frieman adds. In an e-mail toScience, Yuen says his group is well aware of the study's limitations, but writes that absent an animal model, the cell line approach "is all we can do at this moment."
Given the many questions about the epidemiology in the Arabian Peninsula, some researchers are hoping that the genomes of viruses found at different times and locales may yield clues about what is happening, an approach known as genomic epidemiology. So far, viral genomes from four patients have been published: the first reported case, a man who died in Jeddah in June and whose virus was sent to Erasmus MC; a patient who traveled to the United Kingdom in September for treatment; the first case in the U.K. family cluster earlier this year; and one of the Jordan patients, whose virus was obtained and sequenced by a U.S. Navy laboratory in Cairo.
In a recent paper in Emerging Infectious Diseases, a U.K. team published its genomic analysis of the first two cases; team member Andrew Rambaut, an evolutionary biologist of the University of Edinburgh, then updated the analysis on his own Web site after two more genomes became available. The team found considerable variation between the four genomes, and calculations suggest that the virus has circulated since 2011, Rambaut says. In theory, it may have done so only in humans—assuming that many infections were mild and went undetected. But given today's travel patterns, it's unlikely that the virus would remain confined to the Arabian Peninsula if that were the case, Rambaut says. A more likely scenario is that it's circulating in animals and was repeatedly introduced into the human population, he adds—perhaps setting off short human-to-human chains of transmission now and then.
Drosten says that he soon plans to publish his own analysis, which will also include the newly sequenced virus from the Munich patient. In addition, Drosten says that he has an unpublished, partial sequence from a Qatari man who was treated at a hospital in Essen, Germany, last fall. (His group had huge trouble sequencing the genome because the samples contained very little viral RNA.) Drosten's analysis shows that the viruses from Qatar and the United Arab Emirates, which are geographically close, form a separate group—Drosten calls it the "Gulf clade"—from those in Saudi Arabia and Jordan. But he declined to speculate what, if anything, this says about the epidemiology.
Which animal species serves as the springboard to humans isn't clear, and there could be more than one. The viral sequences found so far are closely related to bat coronaviruses, but bat-to-human virus jumps are rare because contact between the two species is uncommon. One notable exception is the Nipah virus, which is believed to cause human disease occasionally in Bangladesh when urine from fruit bats contaminates date palm juice. The alternative is that there is some intermediate animal host, Munster says.
Some anecdotal reports have suggested that livestock acted as that bridge species. German media have reported Clemens Wendtner, a physician at the Schwabing Clinic, as saying that the Abu Dhabi patient owned racing camels—a popular pastime among the Gulf's elite—and that he may have become infected when he visited them shortly before falling ill. The Qatari patient treated in Essen owned a camel and goat farm and told his German doctors that some of his goats had been sick before he fell ill himself; one of his animal caretakers also had a severe cough and was hospitalized.
Only epidemiology studies on the ground can bring more light to many of the questions, Munster says. Whether they are taking place in the four affected Middle Eastern countries is unclear even to WHO, which is trying to stimulate a concerted research effort. "I don't know if WHO has a full handle on all of the studies that are being done or are in the works," WHO spokesperson Gregory Hartl says—and as a human health agency, WHO is not involved in animal studies, he points out. "But we do need to know more about this virus."
Fuente: Science 5 April 2013
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