The hunt for the next potential coronavirus animal host

In 2013, scientists discovered that the intermediate horseshoe bat (Rhinolophus affinis) can carry a coronavirus very similar to SARS-CoV-2, the virus responsible for the pandemic.Some scientists warn there’s a small but real possibility the virus could take refuge in a new animal host and reintroduce it to humans in the future.

AS COVID-19 BLISTERS its way around the globe, much of the focus has been on stopping the spread of the virus and treating those who are sick. But virologists say there’s something else that deserves our focus as well—the search for future animal hosts. Experts say that it’s possible the virus could take hold in a new species and build a redoubt for reinfecting people in the future.

“As the virus is spreading around the world, it might find entirely new reservoir hosts [outside of] China,” says virologist Ralph Baric at the University of North Carolina, Chapel Hill. “We don’t know. It is something every country needs to be thinking about as the epidemics wind down.

Coronaviruses are notoriously promiscuous. Bats host thousands of types without succumbing to illness, and the viruses have the potential to leap to new species. Sometimes they mutate along the way to adapt to their new host; sometimes they can make the leap without changing.

Coronaviruses are known to infect mammals and birds, including dogs, chickens, cattle, pigs, cats, pangolins, and bats. The global health crisis likely started with a coronavirus-infected horseshoe bat in China. From there, the germ possibly jumped to an intermediary species, then jumped to humans. (Read more about how that happens in this zoonotic diseases explainer.)

Virologists are working to predict which species are the most likely potential reservoirs. The risk of the virus taking hold in a new species—and then those animals quietly hosting it for a while before passing it back to humans—is low, says Lin-Fa Wang, a virologist at Duke Global Health Institute in Singapore. But it’s still worth preparing for, Baric says, because the consequences could be a resurgence of the pandemic.

Predicting species

We already know from experience that some pets can become infected with the virus that causes COVID-19. A Pomeranian and a German shepherd in Hong Kong have grabbed headlines by becoming infected; so, more recently, has a domestic cat in Belgium. A Malayan tiger at the Bronx Zoo in New York City became sick with a dry cough in late March and tested positive for the virus, the U.S. Department of Agriculture announced April 5.

Researchers are interested broadly in any animal that the coronavirus could infect, whether or not it causes illness. Though the USDA and the Centers for Disease Control and Prevention say there is currently no evidence that domestic or captive wild animals can spread the novel coronavirus to people, it is important to see if such a thing is possible.

One way virologists can try to predict potential host species is by using 3D computer modelling. For the virus to enter a cell to replicate, a spike-shaped protein it has must bind neatly with an enzyme receptor on the surface of certain animal cells, according to a recent discovery. The receptor, called an ACE2 protein, is the doorknob, and the spike protein is the key that unlocks it. Three-dimensional computer modelling can help figure out which animals have ACE2s that can be “unlocked” by the virus’s spike protein. (See a graphic of how it works here.)

By comparing ACE2 receptors, a March 2020 study identified a number of species that the virus might be able to infect, including pangolins, cats, cows, buffalo, goats, sheep, pigeons, civets, and pigs.

Another way scientists are searching for potential hosts is by exposing cells from various animals to the virus, to see which species can actually become infected. This is what Baric’s lab is doing, with a focus on a variety of animal species in the United States, including livestock. One recent experiment found that cells with ACE2 proteins from humans, horseshoe bats, civets, and pigs could be infected with the virus, while mice could not.

Once it becomes clear which species’ cells can become infected in the lab, it’s necessary to do tests with live animals in a controlled environment, Baric says. To that end, the Friedrich-Loeffler Institut, the German government’s research organization focused on animal health and welfare, is exposing pigs, chickens, fruit bats, and ferrets to the virus to determine whether these species can be infected and whether the virus can replicate in them. If the virus can, the animals would be considered potential reservoirs. Initial results suggest that fruit bats and ferrets are susceptible, whereas pigs and chickens are not.

A similar study, reported this month in a preliminary paper, found that the virus replicates poorly in dogs, pigs, chickens, and ducks, but replicates well in ferrets and cats, with cats capable of spreading the virus in respiratory droplets. This was a lab study, Wang notes, and therefore it doesn’t necessarily mean it will happen in the real world.

Equally important, Baric says, is getting out and testing animals in their natural environments. “Coronaviruses shift host frequently,” he says. “Ultimately you have to go out and survey wildlife.” These types of studies are very hard to do, Wang says, and currently most wild surveys are focused on finding the possible species that spread the virus in the first place, not which species may maintain it in the future.

From human to animals

Of the animals that turn out to be susceptible to the virus, those that humans spend the most time with are the most likely to get infected, says disease ecologist Peter Daszak, president of EcoHealth Alliance. Daszak was part of a virus surveillance team that in 2017 warned about multiple SARS-like viruses in a bat cave in Southern China. More time together means more opportunities for the virus to make the jump from human to animal, he says.

Even if the virus makes the jump to a new species, there’s no certainty it will colonize and persist in that animal, say virologists. There are a lot of factors that have to work out just right for an animal not only to become a host but to become a host capable of re-introducing the virus to humans.

If it turns out the virus could infect a farm animal, it may cause severe illness or multiple deaths. In that case, the virus might be spotted and the outbreak contained. Or the virus may infect the animals and cause nonspecific symptoms, like diarrhea, that are associated with more common diseases. Or it may cause no symptoms at all. The virus could circulate undetected and never jump back to humans—or, in any matter of months, jump back to humans and kick off a renewed outbreak.

The best approach for monitoring, says Daszak, is to strategically test key species for antibodies to the virus—a sign that the animal fought a successful battle against the virus. Luke O’Neill, an immunologist at Trinity College Dublin, Ireland, says antibody tests are cheap and easy. “It is just like a pregnancy test,” he says. “A drop of blood, you can see it within minutes if you have the antibodies or not.”

It’s a “low probability that the virus will go from a sick person back into an animal,” Daszak says. But then again, he muses, “it was a low probability that it emerged in the first place.