Researchers at the Jackson Laboratory and the Trudeau Institute have identified the first mouse strain susceptible to severe COVID-19 without the need for genetic modification. This development, reported in Scientific Reportsmarks a fundamental step in infectious disease research, providing an essential tool to develop vaccines and therapies for future coronavirus variants and potential pandemics.
The CAST/EiJ mouse, part of a research panel that includes eight genetically diverse mouse strains, stands out 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 showed acute illness, highlighting their unique susceptibility to the virus.
“Although most strains of mice have 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 therapeutic therapies. next generation,” said Nadia Rosenthal, scientific director and Professor at JAX and one of the study’s lead authors.
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 as faithful as possible to the mouse genome. This feature makes them an ideal model to investigate severe COVID-19 symptoms in a clean genetic environment.
These mice not only carry high viral loads in the lungs, but also show 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 COVID-19 models.
Initial trials with antiviral treatments have shown promising results, increasing survival rates in CAST mice and raising hopes for their role in developing therapies for future coronavirus outbreaks. As new variants continue to emerge, the CAST mouse model is poised to accelerate a response and provide insights that could ultimately save lives.
Diversity in mouse models offers new perspectives
The study explored eight genetically diverse mouse strains, including A/J, B6J, CAST, 129S1, NSG, NZO, PWK and WSB, spanning 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, JAX research project manager 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-CoV-2 infection. While CAST mice did not recover, some strains did, but showed persistent symptoms resembling long COVID.
“The CAST mice gave us an idea of the acute symptoms of COVID-19, but now we’re going to look at the long-term effects,” Baker said.
In follow-up work, Rosenthal and Baker plan to investigate long-term impacts using this same panel of eight mice.
Overcoming the early challenges of COVID-19 research
When the pandemic began, traditional mouse models were not suitable for SARS-CoV-2 research, as 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 addressed this problem 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 replicated a variety of human-like responses. But these engineered human receptors do not always give a clinically relevant disease phenotype. The CAST mouse is invaluable as its genetic background avoids artificial modifications of the receptor, making it a more natural model for studying severe COVID-19.
“CAST mice are poised to transform COVID-19 research and prepare us for future challenges,” Rosenthal said. “Equally important is the fact that the work reinforces the fundamental role of genetic diversity in science.”