An international team of scientists has assessed the fit for the main cellular attachment point of SARS-CoV-2 in 410 species of vertebrates, including 252 mammals, to categorize those most susceptible to viral entry. The computational study, published in PNAS Monday (August 24), predicts that several critically endangered primate species are at very high risk of the virus, although the results need to be confirmed with further experiments or surveillance.
The receptor for the virus—angiotensin converting enzyme-2, or ACE2—is found in many types of cells and tissues, including in the nose, mouth, and lungs of people. The spike protein that studs the exterior of the viral particle can be compared to a key, ACE2 a lock.
In people, 25 amino acids of the enzyme are important for the virus to gain entry into cells. The scientists behind this latest study used these amino acid sequences to evaluate how suitable the ACE2 protein is for SARS-CoV-2 in other species, for which high quality sequence data for ACE2 existed.
The researchers developed an index that weighted overall amino acid similarity with the residues in human ACE2 known to be important for binding SARS-CoV-2, says senior author Harris Lewin of the University of California, Davis.
The results spotlighted primates such as the Western lowland gorilla, Sumatran orangutan, chimpanzee, and bonobo as at very high risk of infection. This was not unexpected, given that their ACE2 sequence is identical to our own. Monkeys, which are mostly also pegged as very high risk, are known to be vulnerable to COVID-19 and have been used to study the disease, allowing scientists to ask questions about immune memory. Primate facilities have been taking steps since early on in the pandemic to protect their animals from the disease.
The second category (high risk) contained a few surprises, such as three deer species, muskrat, Chinese hamster, and Gambian pouched rat. The similarities for many of these evolutionarily distant taxa “is just an evolutionary quirk,” says Lewin. Also in that category were numerous marine mammals, such as the gray whale, minke whale, harbour porpoise, killer whale, narwhal, and common bottlenose dolphin.
If there is an intermediate species between bats and humans it is likely in the two highest risk categories, which include fewer than 100 species, according to Lewin. He is especially interested in hamsters having compatible ACE2 receptors for SARS-CoV-2 and says wild hamsters might be worth investigating as possible intermediate hosts for transmission of SARS-CoV-2 from bats to humans. Indeed, the Syrian hamster has recently been shown to be a good model for COVID-19 research.
Domestic animals such as cats, cattle, and sheep were at medium risk, and dogs, horses, and pigs were at low risk for ACE2 binding. “Ferrets and mink were in the low risk category, and they have been shown to be susceptible experimentally,” says Lewin. “There’s something we don’t understand about those species.”
It could be that the virus uses a receptor other than ACE2, or that even low-affinity connections and high viral dose can lead to infection. Lewin says the next step now is to infect cells of various species with the virus and to do careful challenge studies with live animals.
“What’s nice is that they looked at a wide range of different species,” says Fabian Leendertz, an infectious disease scientist at the Robert Koch Institute in Berlin. He warns that the results give hints of susceptibility, rather than solid evidence to guide management decisions for places such as zoos. Actual risks can only be confirmed with additional experimental results.
Leendertz was unsurprised that great apes are susceptible, and had warned in March that they are at risk from COVID-19.
Another research group investigated the susceptibility to SARS-CoV-2 infection of 35 marine mammals, again based on how well their ACE2 interacts with the viral spike protein in computer models. They predicted that 15 species would be susceptible.
These studies “cannot predict the outcome of infection, but can predict susceptibility to infection,” explains Graham Dellaire, a molecular biologist at Dalhousie University in Canada, who coauthored the study, posted to bioRxiv August 14. “There are also mitigating circumstances that can make the infection worse or milder in any given organism.” For example, some species might not have ACE2 enzymes in nasopharynx or lung tissues, critical locations for COVID-19 infection and transmission in humans.
For many species, wild or in captivity, it would not be ethical or appropriate to infect them with SARS-CoV-2 in order to observe the outcome. Instead, studies of the ACE2 receptor can flag which species we need to be monitored as potentially vulnerable to infection. It can also inspire cell infectivity experiments.
“We should be more aware in the context of zoos and aquariums about human interactions with these animals,” says Dellaire. “In zoos, we don’t know the consequences of animals getting infected. It could be mild or it could be multi-organ necrosis.” Those who come into close contact with wild animals should also take precautions.
Dellaire warns that sewage discharge into marine environments could expose marine mammals to SARS-CoV-2. There’s some evidence that the virus might survive for more than 10 days at sea, he adds, and contaminated wastewater could concentrate in tidal pools.
RNA from the virus can be detected in wastewater and has even been suggested as a way of monitoring COVID-19 in communities. Lewin says cruise ships need to take extra precautions in discharging sewage at sea.
Many mammal species live in groups, which heightens the risks for them. “Whales and dolphins are in pods and are highly social. With one animal infected, the virus could spread and then adapt and remain in that population,” Dellaire warns.