CAST mouse model: A crucial tool for future COVID-19 outbreaks

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

"Although most mice strains have negligible symptoms from infection with SARS-CoV-2 variants, CAST mice exhibit a lethal response, making them an invaluable resource for studying the virus's impact and testing next-generation therapies," said Nadia Rosenthal, scientific director and professor at JAX, and one of the senior 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 as true to the mouse genome as possible. This characteristic makes them an ideal model for investigating severe COVID-19 symptoms on a clean genetic background.

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

Initial trials using antiviral treatments have shown promising results, boosting survival rates in CAST mice and sparking hope for their role in developing therapies for future coronavirus outbreaks. As new variants continue to emerge, the CAST mouse model stands ready to accelerate a response, providing 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, encompassing traits like type 1 and type 2 diabetes susceptibility, obesity, and leanness. These diverse genetic backgrounds enabled the team to uncover differences in virus susceptibility.

Rosenthal and Candice Baker, director of research projects at JAX and first author of the study, started with all eight strains of mice and found the CAST mouse stood out as a highly susceptible mouse for Sars-CoV-2 infection. While the CAST mice didn't recover, some strains did but displayed lingering symptoms resembling long-COVID.

"The CAST mice gave us insight into the acute symptoms of COVID-19, but now we are going to look at the long-term effects," said Baker.

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 unsuitable for SARS-CoV-2 research, as their cells lack the receptors needed for the virus to bind. In 2023, Rosenthal and her team at JAX and NIH's Rocky Mountain Laboratories addressed this by using mice engineered with human versions of these receptors, but the resulting infections were overly severe and failed to mimic the spectrum of human responses.

By crossing genetically engineered mice with diverse strains, Rosenthal's team replicated a range of human-like responses. But these engineered human receptors don't always give a clinically relevant disease phenotype. The CAST mouse is invaluable, as its genetic background avoids artificial receptor modifications, making it a more natural model for studying severe COVID-19.

"CAST mice stand poised to transform COVID-19 research and prepare us for future challenges," said Rosenthal. "Equally important, the work reinforces the critical role of genetic diversity in science."