The Jackson Laboratory’s Scientific Director Dr. Nadia Rosenthal in her lab. PHOTO COURTESY OF JAX

JAX continues to fight COVID one mouse at a time

By Ezra Sassaman

BAR HARBOR — In January, the Islander spoke to Dr. Nadia Rosenthal of The Jackson Laboratory. At that time, around one year into the pandemic, she hoped her mice might shed light on which genetic tendencies make humans more or less susceptible to SARS-CoV-2, the virus that causes COVID-19. 

Fast forward to September 2021 and Rosenthal’s hopes are closer to fruition. “Host genetics are a significant determinant of coronavirus disease 2019 (COVID-19),” concluded a mid-September preprint of her work. “The importance of the research is we have definitively proven that there are genetic features that affect COVID infection,” Rosenthal explained. 

Rosenthal and her colleagues used mouse survival, weight loss and immune responses as examples of phenotypes (observable traits) that track with genotypes (genetic makeup). Their research showed that mice with the same genetic makeup responded in the same way to SARS-CoV-2 infection. 

Another important genetic tracker were cytokines, which Rosenthal described as the “Paul Revere” of the body. Cytokines warn the immune system about viral invaders and consist of communication molecules the immune system uses to continuously talk to itself and to other parts of the body. 

While laboratory-inbred mouse strains are genetically different from each other in the way that most humans are, members of the same strain are like human identical twins with the same genetics. “This means that if a member of a mouse strain responds to the virus by getting sick, we can predict that any member of this same strain would have the same response in the future,” Rosenthal explained. 

A satisfying part of the project for Rosenthal was verifying her mouse-based research against similar findings of geneticists studying human patients. Both mice and humans exhibit the same kinds of moderate or severe responses to COVID-19. 

Moderate COVID-19 cases for both mice and humans share a “quick-in, quick-out” immune response that flares up rapidly but also draws back in the same rapid fashion. In contrast, slow and steady immune responses lead to more dangerous, severe cases of the virus because they do not subside as rapidly. 

A rapid immune response is particularly important when fighting SARS-CoV-2 and its variants, which are unusually fast at replicating themselves. If a person’s immune system does not immediately prevent the virus from copying itself, it will exponentially increase and wreak havoc on their body. 

Rosenthal used the analogy of armed conflict to explain the immune response to a virus like SARS-CoV-2. If the immune system is a well-trained military operation, it knows how to come in, do a targeted strike and get out. In contrast, if the immune response is poorly orchestrated, “it’s like M*A*S*H,” she explains. “You get casualties and all sorts of collateral damage.” 

Can we predict the severity of human responses to the virus on a genetic basis? Not yet, said Rosenthal. “We still need to first map those genetic features responsible for a moderate response in mice, and then prove their functionality with genetic modification.” 

A complete genetic mapping experiment of this size would take vast amounts of money, space and resources, looking at 400 different randomly generated mice, each with known genetic makeup. “That would be the fastest way to get to specific genetic drivers,” explained Rosenthal. “But even then, it could still take a couple of years.” After that, scientists would need to find a relationship between disease outcome and the occurrence of those same features in human patients. 

In the past, The Jackson Laboratory has been able to challenge different strains of mice directly because they are susceptible to a high fat and high sugar diet causing obesity, for example. But “humanizing” mice – engineering them to be susceptible to COVID – takes a lot of time on its own. 

Research has recently appeared, however, showing some SARS-CoV-2 variants can infect mice directly. This development presents an understandable risk to mice at large in research facilities like The Jackson Laboratory. At the same time, the scientist in Rosenthal sees a silver lining to this news. Genetic mapping would be much quicker without the extra step of engineering mice with human susceptibility to the virus. 

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