Identification of the first mouse strain susceptible to severe COVID-19 without requiring genetic modification

Researchers from the Jackson laboratory and the Trudeau Institute have identified the first strain of mice capable of contracting a severe form of COVID-19 without requiring genetic modification. This development, reported in Scientific reportsmarks a crucial milestone in infectious disease research, providing an essential tool for developing vaccines and treatments against future coronavirus variants and potential pandemics.

The CAST/EiJ mouse, part of a research group including eight genetically diverse mouse strains, is notable for its severe response to SARS-CoV-2 infection, including the beta, omicron, and delta variants. While other strains recovered or showed mild symptoms, CAST mice exhibited acute illness, highlighting their unique susceptibility to the virus.

“Although most mouse strains show negligible symptoms of infection with SARS-CoV-2 variants, CAST mice exhibit a lethal response, making them an invaluable resource for studying the impact of the virus and testing next-generation therapies,” said Nadia Rosenthal, scientific director and professor at JAX and one of the lead authors of the study.

Originally collected on the island of Castania and brought to JAX in 1971, CAST mice were bred at JAX to maintain a genetically pure line, creating a model that was as close to the mouse genome as possible. This characteristic makes it an ideal model to study severe symptoms of COVID-19 on a clean genetic background.

These mice not only carry high viral loads in the lungs, but also exhibit severe lung damage, mirroring the type of hyperinflammatory response seen in human patients with severe COVID-19. This unique strain offers researchers a model that closely resembles the human response to the virus without brain infection – a problem in previous models of COVID-19.

Initial trials using antiviral treatments have shown promising results, increasing survival rates of CAST mice and raising hope for their role in developing therapies for future coronavirus outbreaks. As new variants continue to emerge, the CAST mouse model is poised to accelerate the response, providing information that could ultimately save lives.

The diversity of mouse models offers new perspectives

The study explored eight genetically diverse mouse strains, including A/J, B6J, CAST, 129S1, NSG, NZO, PWK and WSB, encompassing traits such as susceptibility to type 1 and type 2 diabetes, obesity and thinness. These diverse genetic backgrounds allowed the team to discover differences in susceptibility to viruses.

Rosenthal and Candice Baker, director of research projects at JAX and first author of the study, started with the eight strains of mice and found that the CAST mouse stood out as a highly susceptible mouse to SARS infection- CoV-2. Although CAST mice did not recover, some strains recovered but had persistent symptoms resembling long COVID.

“The CAST mice gave us insight into the acute symptoms of COVID-19, but now we will look at the long-term effects,” Baker said.

In follow-up work, Rosenthal and Baker plan to study long-term impacts using this same panel of eight mice.

Overcoming early challenges in COVID-19 research

When the pandemic began, traditional mouse models were not suitable for SARS-CoV-2 research because their cells lacked the receptors necessary for the virus to bind. In 2023, Rosenthal and his team at JAX and the NIH’s Rocky Mountain Laboratories solved this problem by using mice engineered with human versions of these receptors, but the resulting infections were too severe and failed to mimic the spectrum of human responses.

By crossing genetically modified mice with various strains, Rosenthal’s team reproduced a range of human-like responses. But these modified human receptors do not always result in a clinically relevant disease phenotype. The CAST mouse is invaluable because its genetic background avoids artificial modifications to the receptors, making it a more natural model for studying severe cases of COVID-19.

“CAST mice are poised to transform COVID-19 research and prepare us for future challenges,” Rosenthal said. “Equally important, this work reinforces the essential role of genetic diversity in science.”