Rhesus macaques are one animal model for the new coronavirus.Credit: Neil Bowman/Flpa/imageBROKER/Shutterstock

As coronavirus marches around the globe, a sleepy town on the rugged Maine coast has become an unlikely nucleus in researchers’ efforts to combat the disease, known as COVID-19. The Jackson Laboratory, a mouse-breeding facility in Bar Harbor, is rushing to produce stocks of a transgenic mouse that scientists hope will help them to understand the virus.

“We’ve been overwhelmed with requests,” says Cathleen Lutz, a neuroscientist who heads the institute’s mouse repository. The facility has already received orders from around 50 labs for more than 3,000 mice that produce a human version of the protein ACE2, which the virus causing the outbreak, SARS-CoV-2, uses to enter cells. Normal mice seem to be resistant to infection.

The race to unravel the United States’ biggest coronavirus outbreak

With more than 110,000 confirmed human cases worldwide and no sign that the coronavirus is going away, researchers are looking to animals to understand COVID-19. They are testing monkeys, mice and even ferrets to answer key questions about the disease and to fast-track potential drugs and vaccines for clinical trials.

The first results are emerging: teams in China have reported initial findings from infecting monkeys1 and mice2 that have the human ACE2 gene. Labs working on ferrets say they should also have initial results soon: a team led by virologist S. S. Vasan at the Australian Animal Health Laboratory in Geelong has found that the animals are susceptible to SARS-CoV-2. The researchers are now studying the course of infection, before testing potential vaccines. Ferrets are a popular model for influenza and other respiratory infections because their lung physiology is similar to that of humans, and researchers hope they will mimic aspects of COVID-19 in people, such as its spread.

But no animal model is perfect. “There’s going to be a need not just for one animal model, but multiple,” says David O’Connor, a virologist at the University of Wisconsin–Madison. Monkeys and mice tell researchers different things about infection, shedding light on factors such as the role of the immune system or how the virus spreads. “We can try to learn as much as possible as quickly as possible and integrate that with the emerging volume of data from the clinic,” says O’Connor.

Mild illness

O’Connor and fellow University of Wisconsin virologist Thomas Friedrich are part of a loose-knit network of about 60 scientists who are sharing details of their efforts to study the infection in primates and other animals. The pair have not themselves begun testing in monkeys, which they will do with colleagues at a specialized containment facility at the US National Institute of Allergy and Infectious Diseases in Frederick, Maryland. But they were excited to read the first details from experiments in non-human primates infected with COVID-19, reported in a preprint posted online on 27 February.

That research1, led by virologist Chao Shan at the Chinese Academy of Sciences Wuhan Institute of Virology, found that rhesus macaques infected with the coronavirus had a fairly mild illness. None developed fevers, but X-rays of their lungs showed signs of pneumonia similar to those in humans with COVID-19. This was confirmed after some of the monkeys were euthanized and their lungs dissected. The researchers killed two monkeys three days after infection and another pair after six days. They monitored two further animals for three weeks; these monkeys lost some weight, but didn’t seem to have other serious symptoms.

The fact that the monkeys seemed to develop symptoms similar to those in people with mild forms of COVID-19 is an important takeaway, says O’Connor. To find better models for more severe human infections, researchers will have to look at different animals and vary other experimental factors, such as the route by which the virus is administered, he adds. But because monkeys have similar immune systems to humans, they will be useful for testing how our bodies cope with the virus. There are signs that a person’s own immune response can worsen some diseases, such as influenza and severe acute respiratory syndrome (SARS), says Friedrich. Monkeys will help to establish whether this is the case for COVID-19.

Another pressing question that researchers will try to address in monkeys is whether the virus can hide in certain organs in individuals ostensibly cured of infection. The existence of such reservoirs might explain anecdotal evidence that some people have been re-infected with the coronavirus after recovering, Friedrich says.

Rodents revisited

Many researchers trying to understand COVID-19 are turning to a stalwart of animal research — the lab mouse — to test drugs and vaccines, and to investigate the nature of the infection. The rodents that Jackson Laboratory is breeding, known as humanized ACE2 (hACE2) mice, were developed in response to the 2002–03 outbreak of SARS, which is caused by a virus related to the current coronavirus3,4.

But as interest in and funding for SARS research waned, many labs stopped working with the mice, says Stanley Perlman, a coronavirologist at the University of Iowa in Iowa City whose lab developed one of the strains3. That’s all changed now, he says: “Everybody wants these mice. Nobody really has them.”

Jackson Laboratory did not maintain an hACE2 mouse colony before the current outbreak. But it is now establishing one, beginning with vials of mouse sperm provided by Perlman. The first pups were born last week, and Jackson plans to begin supplying researchers in May, says Lutz. “There are biological issues that are standing between us and delivering mice — and that’s gestation.”

Among those on the waiting list for hACE2 mice is Michael Diamond, a viral immunologist at Washington University in St. Louis, Missouri. He and his team hope to use the mice to test vaccines and antibody-based treatments. They also aim to use CRISPR gene editing to identify genes that make mice either more susceptible or resistant to infection.

While Diamond and his team wait, they are developing other mouse models. In one set of ongoing experiments, they are trying to imbue mice with the human version of ACE2 using a virus as a carrier. In another, they have infected mice that have compromised immune systems with SARS-CoV-2. The hope is that the virus, after repeated passage through these mice, will gain mutations that help it to infect rodents with healthy immune systems. Diamond says the same approach worked with Zika virus, another pathogen to which mice are not naturally susceptible.

Starting point

At least one lab with access to existing colonies of hACE2 mice has already begun infecting them with coronavirus. A team of researchers in China described initial results from infecting thesemice in a preprint posted on the bioRxiv server last month. The mice, like rhesus monkeys, seemed to develop only mild illness, showing weight loss and signs of pneumonia but nothing more severe. Qin Chuan, a virologist at Peking Union Medical College in Beijing who co-led the study, says the animals should be useful for countering SARS-CoV-2. The researchers also identified immune responses in infected mice that could guide vaccine development. And, in unpublished work, his team identified several drugs that slowed the virus’s replication and limited the animals’ weight loss.

Animals that develop only mild infections could be useful for testing drugs and vaccines, but they might not help scientists understand more severe cases, says Perlman. “It doesn’t really tell you much about how the virus causes disease.” He says he will try infecting hACE2 mice — when he can get them — but he’s already thinking about developing other mouse models to better mimic severe cases. The existing mice have both human and mouse versions of the ACE2 gene, so one possibility is eliminating the mouse version.

“A lot of the models are imperfect; we do the best we can,” Perlman says.