How Ebola Adapted to Us

During the recent record-breaking outbreak, the virus picked up a mutation that made it better at infecting human cells.

Ebola virus particles (blue) budding from an infected cell.  (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

In December 2013, in a small village in Guinea, the Ebola virus left its traditional host—probably a bat—and infected a young boy. That leap triggered what became the largest Ebola outbreak in history. At first, the virus stayed within Guinea’s borders and, as in every previous epidemic, affected just a few hundred people. But in the spring of 2014, that gentle simmer came to a disastrous boil. Cases skyrocketed as the virus spread to Sierra Leone, Liberia, and other countries. By the time it was finally brought to heel in 2016, more than 28,000 people had been infected and 11,000 of them were dead.

The unprecedented scale of the outbreak gave the virus ample opportunities to adapt to its new human hosts—and it took advantage of them. Two independent teams of scientists have shown that in early 2014, Ebola virus picked up a mutation called A82V, which made it worse at infecting bat cells, but better at infecting human ones. And once viruses with that mutation appeared, they quickly took over. They were the ones that spread beyond Guinea, the ones responsible for the vast majority of cases, the ones that landed in a Texan emergency room.

Both groups emphasize that the mutation may not have caused the virus’s exponential spread. “Its appearance coincided with the virus taking off, but others factors were probably more important, like the movement of infected people into urban areas and lack of proper burials,” says Jonathan Ball from the University of Nottingham, who led one of the teams. “If we hadn’t seen that mutation, there would probably still have been a big outbreak.”

Still, it’s clear that the virus can adapt to humans if given half the chance. “That mutation happened several months into the outbreak, and would never have happened if we had stopped the virus early,” says Pardis Sabeti from the Broad Institute, who co-led the other group. “It’s a reminder of the importance of working fast, and not letting these viruses have a lot of opportunities to reproduce in humans and adapt to them.”

Until recently, many researchers doubted that Ebola was adapting to people at all. “The word on the street was no. The conclusion has been that Ebola is Ebola is Ebola,” says Jeremy Luban from the University of Massachusetts Medical School, who worked with Sabeti. “There was no obvious evidence that there was anything special about the viruses that recently killed so many people.”

He found such evidence by comparing the genomes of almost 1,500 Ebola viruses from the outbreak. These belonged to two main lineages—one that began the epidemic and stayed within Guinea, and another that replaced it and spread further afield. The latter strains evolved from the former, and differed from their ancestors by a couple of mutations. One of these, A82V, looked like it was especially important, because it affected small molecules called glycoproteins on the virus’s surface.

If you look at Ebola under a microscope, you’ll see a long, knotted tube, covered in tiny studs. Those are the glycoproteins. They fit into a host cell like a key into a lock, and in doing so, they open the door to an infection. And the A82V mutation seemed to change the shape of the key. “It’s in in exactly the part of the glycoprotein that interacts with the host cell,” says Luban. “That’s an extraordinary coincidence. It’s hard to brush off.”

To see how that mutations affected the virus, Luban’s team isolated the glycoproteins and fused them to the empty shell of another virus. The result was a fake virus that looked outwardly like Ebola but that couldn’t ever reproduce or spread (and so was easier to work with safely). And when these fake viruses bore the mutant glycoproteins, as opposed to the standard versions, they became 2 to 4 times better at infecting human cells.

By coincidence, Ball’s team had been doing similar experiments. They looked at a wider range of mutations, and they used their own brand of fake viruses. But their conclusions were the same: A82V doubles the Ebola virus’s ability to infiltrate human cells.

And not just humans, either. Luban’s team showed that mutant viruses are also better at infiltrating the cells of chimps and monkeys, but not those of dogs, cats, rats, and mice. Meanwhile, Ball’s team showed that they were actually worse at infecting the cells of bats, their typical hosts. It seemed that over the course of the outbreak, Ebola evolved from a virus that excels at infecting bats into one that’s better at infecting humans.

“When you have two groups that come up with the same finding, it’s hard to argue with that,” says Lisa Hensley from the National Institute of Allergy and Infectious Disease. “[The mutation] certainly seems to have made the virus more adapted to human cells,” at least in laboratory experiments.

How so? Remember that glycoprotein is like a key, which fits into molecular locks on a host cell. Ball thinks that A82V tweaks the shape of the key, making it a better fit for human-shaped locks. Luban thinks that A82V makes the key easier to turn, allowing it to more readily start the process of infection. Both are planning experiments to test their respective ideas. “We’ve got a beer on the outcome,” says Ball.

The bigger question is this: How did A82V influence the course of the recent epidemic? Did an improved ability to enter human cells also change the virus’s skill at spreading, reproducing, or killing? Does that explain why so many more people were infected and killed than in previous flare-ups?

None of the evidence is conclusive. People who were infected with the mutant strains were 27 percent more likely to die than those with the original versions, but that could well have been due to poor access to healthcare. The mutant strains arose shortly before the outbreak took off, but also at a time when infected people were moving into highly populated urban areas. “It isn’t possible to determine definitively if these mutations are responsible for the changes in scale and length of the most recent epidemic,” says Anne Rimoin from the University of California, Los Angeles.

So far, both teams have only tested their viruses on cells in laboratory dishes, and neither have actually worked with Ebola proper. To see if A82V really makes a difference, they’ll have to test different strains of the actual virus on live monkeys. That’s challenging, says Hensley, and not just because such studies can only be done in the most stringent biosafety laboratories. “[Ebola] is already so lethal,” she says. If a mutation slightly increases the virus’s lethality, “would you be able to pick that up? We won’t know until we try.”

It’s also worth remembering that even without A82V’s influence, Ebola is already reasonably good at infecting humans and spreading between us. Perhaps that’s because some strains in bat populations already have mutations that make them better at jumping into humans, says Sara Sawyer from the University of Colorado, Boulder. “These human-specific adaptations could have effects that dwarf those found in the current studies,” she adds.

To test this idea, “we would need to compare Ebola isolates from humans and from the reservoir animals,” says Sawyer. “Such studies have not been possible because we don’t have any Ebola viruses from bats, and we don’t even know for sure that bats are the reservoir."

Whatever the reservoir is, that’s where Ebola is currently hiding. The outbreak has been stopped, and the A82V strains have likely disappeared. Maybe they’ll be back. Maybe the next outbreak will feature a different set of mutations that benefit the virus as it spreads between humans. Either way, says Rimoin, “these papers highlight the necessity for vigilance, constant monitoring of emerging infectious diseases, and a rapid response to prevent the ability of the virus to adapt to humans.”

That’s a lesson that applies beyond Ebola, says Ball. “You can’t ignore the fact that these viruses evolve and become better adapted to human infection,” he says. “We’ve kind of ignored the MERS coronavirus, which is still rumbling along in the Arabian peninsula. It’s endemic in some camel populations, and there are constant spillover events into humans. For the moment, that doesn’t go very far, but you can’t always rely on that lottery to come down in your favor.”