o much of the world, the virus behind the devastating Ebola outbreak in Africa seems to have stormed out of nowhere. But Leslie Lobel thinks we should have seen it coming. In 2012, Lobel and a team of researchers spent six months in Uganda studying the Ebola virus and related viruses. Over the course of their stay, these pathogens caused at least four separate outbreaks of disease in central Africa, affecting more than 100people. To Lobel, a virologist at Ben-Gurion University of the Negev in Beer-Sheva, Israel, the outbreaks felt like the small tremors that can precede a major earthquake. “We all said, something is going on here; something big is going to happen,” he says. Like Lobel, other scientists have predicted that these viruses would one day cause a major epidemic — and the current outbreak, which has so far killed nearly 5,000 people, has proved them right. There are five species of closely related viruses that scientists refer to as ‘ebolavi-ruses’; the species behind the current outbreak, Zaire ebolavirus, is more generally known as ‘the Ebola virus’. Along with Marburg virus and Lloviu virus, the ebolaviruses make up the filovi-ruses, a family that was unknown before the 1960s. All of the filoviruses share a common structure, and most of them cause life-threatening haemorrhagic fevers in humans. Research on these once-ignored viruses took off after the 2001 anthrax attacks in the United States, which prompted officials to sink money into investigating lethal pathogens that might be used in bio-terror attacks and to build dedicated laboratories where they can be TCENTRE FOR INFECTIONS/PUBLIC HEALTH ENGLAND/SPLAn Ebola virus particle from the 2014 outbreak.THE EBOLA QUESTIONSScientists know a lot about the virus that causes Ebola — but there are many puzzles that they have yet to solve.BY ERIKA CHECK HAYDEN 554 | NATURE | VOL 514 | 30 OCTOBER 2014FEATURENEWS© 2014 Macmillan Publishers Limited. All rights reservedsafely studied. Scientists have learned how these viruses work and have created the first experimental vaccines and therapies that might stop them. “The biodefence funding has been huge,” says microbiologist Thomas Geisbert of the University of Texas Medical Branch at Galveston, who has studied ebolaviruses for 26 years. But the advances in knowledge about filoviruses have also exposed the gaps. Scientists suspect that more members of the filovirus family remain to be discovered and in other parts of the world. They are also working to understand which animals naturally harbour filoviruses and why human filovirus outbreaks seem to be rising in frequency: they have occurred in 19 of the past 21 years, and three times this year alone. Finding answers is difficult because outbreaks are unpredictable and laboratory work with filoviruses requires the highest security measures.In the past few months, research has necessarily taken a back seat to efforts to control the Ebola outbreak—but as the epidemic escalates, science is coming to the fore. Researchers are recognizing that they might be able to stop this Ebola virus only if they understand its biology and how to control it. “We need a lot more information about the virol-ogy, the clinical presentation and the epidemiology of this virus,” says Michael Osterholm, a public-health scientist at the University of Minne-sota’s Center for Infectious Disease Research and Policy in Minneapolis. “Nobody underestimates the difficulty of doing that research in these settings, but it is really important to get this information.” With this in mind, Nature asked leading researchers to discuss the most urgent scientific questions about the Ebola virus and other filoviruses — the questions that, if answered, might prevent another disastrous outbreak, or help to contain the current one. This is what they said.WHERE DO FILOVIRUSES COME FROM?In July 2007, a miner who had been prospecting for lead and gold in a Ugandan cave became infected with Marburg virus. Officials closed the cave, and a team of researchers led by the US Centers for Disease Control and Prevention (CDC) swept in to investigate. They hoped to answer a decades-old question: what animal is the natural host for filo-viruses? The mystery had lingered since 1967, when Marburg virus — the first filo virus to be discovered — sickened European lab workers who had handled imported monkeys. The high lethality of filovirus infec-tion in monkeys, humans and other apes suggested that primates were not the natural hosts: if a virus kills too many of its hosts, then it cannot propagate and dies out. There were clues that bats might be the ‘reservoir’ species. But to prove it, scientists needed to find an infected bat. The researchers captured some 1,300 bats roosting in the cave and tested their blood for Marburg virus1. They finally found what they were looking for: infectious Marburg viruses isolated from five Egyptian fruit bats, none of which showed symptoms of disease. The team also found more infected bats in a nearby cave that had been linked to a previous Marburg virus outbreak.It is not entirely clear how the virus is transmitted from bats to people, although the most likely route is through contact with bodily fluids. Bats infected with Marburg virus in the lab shed the virus in their mouths, so wild bats might spread it by leaving traces on fruit that is later eaten by other animals2. Knowing the host species for the other filoviruses is crucial. “Until we understand what that reservoir is, it is difficult to limit your encroachment on that species,” says virologist John Dye of the US Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland.Researchers now strongly suspect that bats are the natural host for ebolaviruses, too. In 1976, during one of the first known Ebola outbreaks, the six people who were initially infected worked in a factory room in Sudan that was home to roosting bats3. Researchers have since isolated antibodies to ebolaviruses from bats, as well as snippets of genetic ma terial from the viruses. But proving that bats are the reservoir has been maddeningly difficult — no one has isolated an infectious ebola-virus from a wild bat, and it has been difficult to trace rare and sporadic outbreaks back to a source. The ebolavirus outbreaks have originated in many locations, only sometimes among people or animals who have had contact with bats. “You’re pretty much looking
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