Expediting COVID-19 research

The Jackson Laboratory is delivering a unique transgenic mouse model to the world’s research community

The world is waiting for vaccines and treatments to mitigate the spread and severity of the coronavirus COVID-19 pandemic. The Jackson Laboratory (JAX) is working to ensure that the worldwide research community has access to a mouse model that can serve as an accurate experimental platform for COVID-19.

Very shortly, there will be thousands of these mice available to the scientific community.

Scientists depend on animal models for the development and testing of safe and effective vaccines as well as antiviral and other therapeutic strategies. However, standard inbred strains of mice are not susceptible to infection by SARS-CoV-2, the virus that causes COVID-19, says Cat Lutz, Ph.D., senior director of the JAX mouse repository and in vivo pharmacology. “There's a big enough difference between the ACE-2 receptor in mice versus the ACE-2 receptor in humans,” she explains. This means it’s necessary to genetically engineer a mouse model that's capable of being infected.

Fortunately, that engineering work was already done. A 2002 outbreak of a related coronavirus, known as severe acute respiratory syndrome (SARS), led many in the research community to realize that “this is probably not going to be the last time we’re going to be faced with a coronavirus infection that is going to be pandemic within the population,” Lutz says. In 2007 Stanley Perlman and Paul McCray of the University of Iowa developed the K18-hACE2 mouse, which carries the hACE2 (human angiotensin I converting enzyme 2) gene; this is the gene that encodes the receptor that the COVID-19 binds to, infecting cells and causing illness.

JAX has a special role in maintaining and distributing genetically defined mouse models to the worldwide scientific community. When the COVID-19 crisis arose, it became clear that there would be high and immediate demand for the mouse model.

“Right now, we're going from zero to a hundred miles an hour,” Lutz says. “We started with getting a small vial of sperm from Stanley Perlman, who very generously and very graciously understood the urgency of the situation and released that to us immediately. He then released another 15 vials that we got from his laboratory.”

To generate sufficient quantities of the K18-hACE2 mice, the JAX team immediately initiated a large-scale in vitro fertilization (IVF) program. “We are extremely fortunate to have reproductive science capabilities that far extend our capacity to generate these mice by just natural mating,” Lutz explains. “Natural mating involves putting a male and a female into a cage, giving them some time to get to know each other, and producing a small litter of pups of maybe five or six animals.”

By using IVF alongside traditional breeding, JAX has generated a new colony of hACE2 mice. The colony can now be sized to meet the demands of researchers around the world.

Preliminary data, from multiple independent research institutions that have recently received cohorts of hACE2 mice from JAX, indicate that the mice are not only capable of infection by SARS-CoV-2, but also lose body weight as a result of a sustained infection that is lethal in these mice. This is similar to the results from previous research seen with SARS-CoV infection. Moreover, genetically identical mice that did not receive the virus show no signs of illness.

Lutz notes that all this extraordinary effort is more expensive to conduct than traditional breeding. “But one thing that we have committed ourselves to doing is to making sure that the price of the mice is as low as it can possibly be. This is very much in line with our nonprofit mission. We do want to lend some reassurance to the users of these animals that we are providing them not only as quickly as possible, but as cost-effectively as we possibly can, so that they can maximize the use of these animals in their research.” Thanks to the cooperation of the University of Iowa, JAX is also keeping licensing costs associated with the mice to a minimum.

Besides the efforts to breed and distribute enough K18-hACE2 mice to meet demand, JAX is reviewing other mouse models for their potential to advance COVID-19 research.

Lutz adds, “I think that the work we're doing with COVID-19 really speaks to the strengths of The Jackson Laboratory. I don't imagine that there are many institutions who could be called into action in the way that we have been, and responded as quickly as we have. We certainly have an excellent staff of individuals. Our nonprofit mission resonates throughout the institution, especially at times of crises like these. And I think we feel very privileged to be able to participate and facilitate the work that really needs to happen, to get the country and the world through this crisis at this time.”