In just a few months, the ongoing COVID-19 pandemic has put billions of humans at risk. But as researchers work around the clock to understand SARS-CoV-2, the virus behind the disease, some have begun to worry that countless others may be at stake: animals who could catch the germ from their distant Homo sapiens cousins.

Recent reports of SARS-CoV-2 infecting creatures such as monkeys, dogs, ferrets, domestic cats and even a tiger have raised the possibility that the pathogen could plague other species—including, perhaps, ones already imperiled by other, non-infectious threats.

Though researchers suspect the virus originated in a wild creature such as a bat, they stress that humans remain the virus’ most vulnerable victims, as well as the hosts most likely to spread the disease from place to place. There is also no evidence that animals are passing the pathogen to people, says Jane Sykes, a veterinarian and animal virus researcher at the University of California, Davis. However, studying the creatures this stealthy virus has affected so far could help scientists understand what makes some species—but not others—susceptible.

A useful molecular “key”

Coronaviruses are notoriously indiscriminate infectors. The number of different coronaviruses that exist in the wild number in at least the hundreds, with most likely inhabiting the bodies of bats. On the whole, members of this large family of viruses seem very capable of frequent hops into new species, including humans, making recent detections of SARS-CoV-2 in non-human animals somewhat unsurprising, says Linda Saif, a virologist and animal coronavirus expert at Ohio State University. Already, a commonality in these cases has emerged: the molecular compatibility of the virus with its host.

To infect a cell, a virus must first break in. This encounter typically requires the pathogen to fit itself into a specific molecule, called a receptor, on the surface of its target cell. It’s a bit like a key opening a lock. Not all viral keys will work on a given cell’s lock, but the better the fit, the more easily the virus can gain access.

Unfortunately for humans and our animal relatives, SARS-CoV-2’s key, called spike protein, is a multifunctional tool. It homes in on a cellular lock called ACE2—a blood pressure-regulating protein thought to be universal among vertebrates, the group that includes mammals, birds, reptiles, amphibians and fish, says Jim Wellehan, a zoologist and microbiology at the University of Florida’s College of Veterinary Medicine.

Millions of years of evolution have subtly tweaked the shape of ACE2 in each of these lineages. But in domestic cats and several primates, the regions of ACE2 that bind to SARS-CoV-2’s spike protein look nearly or completely identical to the vulnerable human version.

The case in cats

Such molecular similarities may help explain why a cat in Belgium and another in Hong Kong, each under the care of owners who fell ill with COVID-19, reportedly tested positive for the virus in March. During the SARS outbreak that began in 2002, SARS-CoV-1—a similar coronavirus that also uses ACE2 to enter cells (albeit less effectively than SARS-CoV-2)—also hopped from sick humans into domestic felines.

Sykes says these isolated incidents shouldn’t be cause for alarm. Although a recent study in the journal Science corroborated that cats can contract SARS-CoV-2 when experimentally dosed with large amounts of virus, pets probably aren’t getting seriously sick very often in the real world, she says. (If they were, we’d probably know by now.)

Great news from the @BronxZoo!



Stick around tonight after The Zoo to hear from Dr. Paul Calle, Dr. Jeff Young and @ForrestGalante about the connection between animals and COVID-19. pic.twitter.com/W6DdK7dmGb — Animal Planet (@AnimalPlanet) April 11, 2020

The felines most at risk, Sykes says, are probably those in the company of sick owners, who may be exposing their pets to high quantities of viral particles. Even then, infection isn’t a guarantee. Another recent study, which has yet to be published in a peer-reviewed journal, found no evidence of the virus in a group of cats and dogs that had spent several weeks cooped up with several SARS-CoV-2-infected humans. Large surveys in places like Hong Kong, the United States and South Korea have borne out similar results: thousands of pet cats, as well as horses and dogs , tested negative for the new coronavirus. (But another study—also not peer-reviewed—did find antibodies against the virus in some feral felines from Wuhan, China, hinting that the animals may have encountered the pathogen before.)

There’s also no evidence that infected cats can shuttle the virus into humans, Sykes says. And while the researchers behind the new Science study noted that cat-to-cat transmission was possible in confined laboratory spaces, these artificial settings are poor proxies for the natural world, she says. Just because an animal can harbor a virus in its body doesn’t mean it will be good at spreading the pathogen.

Findings in domestic cats don’t always translate into other species, even closely related ones. Earlier this month, a Malayan tiger named Nadia at the Bronx Zoo made headlines when she tested positive for SARS-CoV-2. Though the cause remains unclear, zoo personnel suspect an infected keeper unwittingly passed the pathogen to the tiger during routine care, triggering a dry cough and diminished appetite in the big cat. (A handful of other tigers, as well as a trio of lions, seemed slightly ill as well, but weren’t tested.) A vulnerable ACE2 molecule might explain Nadia’s spate of mild symptoms. But more than 10 million years of evolution separate domestic cats from their wild tiger kin—and the two species aren’t always susceptible to the same diseases.

The rest of the equation

A recent mouse study reinforces the importance of ACE2 in the spread of the new virus. These rodents’ version of ACE2 is pretty dissimilar to ours, making them resistant to the new coronavirus; only when genetically engineered to express human ACE2 do mice fall ill. Yet other animals with less human-like variations of ACE2, including dogs and ferrets, can be vulnerable to the new coronavirus without any genetic rejiggering. “ACE2 is not the whole story,” Saif says.

Another influential factor in cross-species transmission is probably proximity. Even if a creature’s molecular makeup isn’t perfectly compatible with the pathogen, frequent exposures to humans harboring the coronavirus could eventually sicken a small percentage of the population.

This scenario may be what has played out in dogs, who seem to be poor hosts for the new coronavirus, according to the recent Science study. Some 470 million canines are kept as pets, and almost none appear to have caught SARS-CoV-2 naturally: So far, only two pups—a Pomeranian and a German shepherd, both in Hong Kong—have tested positive for the pathogen.

Ferrets present a curious case as well. While their ACE2 receptors don’t seem to be a perfect fit for the new coronavirus, the germ can take hold in their lungs. Researchers have known for decades that the airways of these weasel-like mammals make them susceptible to several infectious respiratory illnesses that affect humans, including the flu and the original SARS, Saif says. SARS-CoV-2, another lung-loving microbe, is no exception. Stricken with the germ, ferrets come down with fevers and coughs, helping spread the pathogen when in close contact.

Still, anatomical similarities can’t fully explain why viruses find success in certain mammals. Guinea pig airways, for example, also bear some resemblance to ours, but these rodents don’t always experience disease like we do. That leaves the full story of ferrets’ odd viral vulnerabilities somewhat mysterious, Saif says. Perhaps the ferret immune system is easily duped by the virus and struggles to purge the pathogens early on during infection.

Our closest companions

With these preliminary findings in hand, pet owners worldwide are understandably worried about their furry family members. Sykes encourages them not to fear contagion and instead foster solidarity with our animal kin.

“It’s important we emphasize that human-to-human transmission is what’s driving this pandemic,” she says. “People need to be enjoying the human-animal bond, rather than thinking about abandoning their pets.”

Still, Sykes and other experts advise caution around pets, especially for owners who have reason to suspect they’ve been infected with the new coronavirus. The CDC recommends treating cats and dogs as you would any other family member: self-isolating for the duration of an illness to avoid the spread of disease. Pet owners should also try to ensure their furred companions comply with physical distancing measures as much as possible, Saif adds, which means keeping them indoors and limiting contact with people and animals outside their own households.

Keeping wild animals wild

A handful of studies have begun to survey other species for susceptibility to the new coronavirus. So far, the virus appears capable of infecting bats—the suspected original animal source of the pathogen—as well as golden Syrian hamsters, but struggles to replicate in the bodies of chickens, pigs and ducks.

With more than 6,000 species of mammals inhabiting the globe, these lists are by no means comprehensive. But researchers are unlikely to get answers about other animals until they test them directly, says Smita Iyer, a virologist and immunologist at the University of California, Davis. “With new viruses like these, you just don’t know what you don’t know.”

Nevertheless, researchers have begun to take precautions against the possibility that the virus will move not from animals into humans, but the other way around. “The major vector [of disease] is us,” says Wellehan, who interacts with several mammalian species including bats in his work. “I don’t see them as a threat. I see them as potential victims.”

Should humans accidentally carry SARS-CoV-2 back into the wild, the effects could be catastrophic, especially if a threatened or endangered species contracted severe disease. Concerns about our vulnerable great ape cousins, who harbor coronavirus-friendly versions of ACE2 on their cells, have already prompted conservation sites and parks to shutter.

Zoos that house wild cousins of species already shown to be vulnerable are also adopting new safety measures. At the Smithsonian’s National Zoo, keepers are donning extra protective equipment and practicing extensive physical distancing around primates, felids (the group that includes wild cats such as tigers, lions and cheetahs) and mustelids (relatives of ferrets, such as otters). Also being monitored are animals such as civets, the small, cat-like mammals that played a crucial role in the SARS outbreak nearly two decades ago.

Guarding these species from infection isn’t an easy process, says Don Neiffer, the National Zoo’s chief veterinarian. Amidst a pandemic, resources are limited, he says, and some of the changes have been especially difficult for active species that spend a lot of their time engaging in play with keepers. However, Neiffer stresses, these measures are in place to maximize protection for as many species as possible for the duration of the outbreak.

By keeping wild animals safe, we’re also protecting ourselves. Even if most other animals don’t experience severe forms of COVID-19, Saif says, they could quietly harbor the pathogen in their bodies. The virus might then be poised to reenter the human population in the future, sparking another devastating outbreak.

The breadth of the SARS-CoV-2’s evolutionary reach should be an eye-opener, Iyer says. Cross-species transmissions happen in all directions: animal to animal; animal to human; and human to animal. These jumps brought us the pandemic in the first place, she says, and should be a cautionary tale for people as they continue to encroach on and destroy the world’s wild spaces.

“We might want to start with the basics” and respect the territory of our neighbors out in nature, Iyer says. “There’s a reason they’re called ‘wild’ animals.”