Researchers at The Jackson Laboratory (JAX) and the Trudeau Institute have made a groundbreaking discovery in the field of infectious disease research by identifying the first naturally susceptible mouse strain to severe COVID-19. This strain, the CAST/EiJ mouse, is crucial for developing effective vaccines and therapeutics for future coronavirus variants and potential pandemics. Published in Scientific Reports, the research marks a major step forward in understanding how different genetic backgrounds impact the severity of SARS-CoV-2 infections.
The CAST/EiJ Mouse: A Unique Model for Severe COVID-19
The CAST/EiJ mouse stands out within a panel of eight genetically diverse mouse strains studied for their response to SARS-CoV-2, which includes variants such as beta, omicron, and delta. While most other strains either showed mild symptoms or recovered from the virus, the CAST mice exhibited a severe and often lethal response. This distinctive susceptibility positions the CAST strain as a valuable model for studying acute COVID-19 symptoms and for testing new treatments aimed at combating the virus.
Nadia Rosenthal, scientific director and professor at JAX, and one of the senior authors of the study, explained that while many mouse strains experience negligible symptoms when infected with SARS-CoV-2, CAST mice offer a critical opportunity to study the virus’s most severe effects. “CAST mice exhibit a lethal response, making them an invaluable resource for understanding the virus’s impact and for testing next-generation therapies,” Rosenthal said.
Originally collected in 1971 from the island of Castania, CAST mice were bred at JAX to maintain a genetically pure line. This purity is essential for studying the virus’s effects on a clean genetic background, ensuring that any findings are as representative as possible of natural genetic variation. In addition to their severe response to the virus, CAST mice also show high viral loads in the lungs and severe lung damage, symptoms that mirror the hyperinflammatory response seen in human patients with severe COVID-19.
A Model for Future Therapeutic Development
The discovery of the CAST mouse as a natural model for severe COVID-19 has important implications for the development of antiviral treatments. Initial trials using antiviral drugs have demonstrated promising results, improving survival rates in CAST mice. These early successes underscore the potential of the CAST model to accelerate research into therapies for future coronavirus outbreaks. Given the continuous emergence of new variants, such a model is invaluable in ensuring a timely and effective scientific response.
Rosenthal and her team are hopeful that the CAST mouse will help inform the development of treatments that can mitigate the severe symptoms seen in human patients, particularly as new viral variants evolve. The model’s ability to replicate many aspects of severe COVID-19, without brain infections—an issue seen in other models—makes it especially valuable for research. “The CAST mouse model is poised to play a key role in responding to future pandemics,” said Rosenthal.
Exploring Genetic Diversity in Mouse Models
The research conducted by Rosenthal and Candice Baker, director of research projects at JAX and the study’s first author, highlighted the importance of genetic diversity in understanding how different strains of mice react to the virus. By examining a wide variety of mouse strains, including A/J, B6J, CAST, 129S1, NSG, NZO, PWK, and WSB, the team gained insights into the role of genetic factors in virus susceptibility. These strains, which also carry traits like susceptibility to type 1 and type 2 diabetes, obesity, and leanness, helped researchers identify the CAST strain as particularly vulnerable to SARS-CoV-2 infection.
While some other strains of mice displayed lingering symptoms that resembled long-COVID, CAST mice did not recover, providing a more acute perspective on the virus’s immediate impact. This distinction is important because it allows scientists to study the early, intense effects of COVID-19 while opening the door for future studies on the long-term effects, such as the post-acute sequelae of SARS-CoV-2 infection (PASC), or long-COVID.
“We are just beginning to explore the long-term effects of COVID-19 in these diverse mouse strains,” Baker noted. “The CAST mice gave us vital information about the acute symptoms of the disease, and now we plan to investigate the lasting consequences.”
Overcoming Early Research Challenges
At the start of the COVID-19 pandemic, traditional mouse models were largely ineffective for studying the virus due to the lack of receptors required for SARS-CoV-2 to bind and enter cells. In response, scientists at JAX and the NIH’s Rocky Mountain Laboratories engineered mice with human versions of these receptors, enabling them to become infected. However, these genetically modified mice often exhibited an overly severe form of the disease, which did not accurately reflect the broad spectrum of responses observed in human patients.
By creating genetically diverse mouse models that include these human receptors, Rosenthal’s team managed to replicate a range of human-like responses. However, the engineered receptors sometimes failed to produce a clinically relevant disease phenotype. This is where the CAST mouse offers a distinct advantage: its natural genetic makeup provides a more accurate and representative model for severe COVID-19, without the need for artificial modifications.
The use of genetically diverse mice, including the CAST strain, has allowed researchers to avoid the complications introduced by receptor modifications, providing a more natural platform for studying the virus. “CAST mice have opened new doors for COVID-19 research, offering a more authentic model of the disease,” said Rosenthal.
The Road Ahead: Investigating Long-Term Effects and Future Challenges
Looking ahead, the team at JAX and Trudeau Institute plans to continue investigating the long-term effects of COVID-19 using the same panel of eight genetically diverse mice. This follow-up research is crucial as scientists continue to unravel the complexities of long-COVID, which can cause persistent symptoms such as fatigue, difficulty breathing, and neurological issues.
Additionally, the CAST mouse model’s ability to mimic severe COVID-19 symptoms makes it an invaluable resource for testing new antiviral drugs and vaccines. As future coronavirus variants emerge, the CAST mouse model stands ready to play a pivotal role in accelerating responses to new outbreaks, offering scientists insights that could ultimately save lives.
“CAST mice are poised to become a critical tool in our ongoing battle against COVID-19 and future pandemics,” Rosenthal concluded. “This research underscores the importance of genetic diversity in science and its ability to provide fresh perspectives on complex diseases.”
Source: Jackson Laboratory