Why are some COVID cases more severe?

'Humanized' mice offer a clue.


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Since Covid-19 started, many research studies have quoted that 80 to 90% of people infected with COVID-19 experience only mild cases. Still, the question remains, why do those 10 to 20% face more severe or life-threatening symptoms?

Researchers in the lab of Yale’s Richard Flavell decided to pose this question to a mouse, or rather to mice they have engineered to possess human-like immune systems.

These “humanized mice” revealed that the causes of severe COVID may lie in our antiviral inflammatory response to the virus, the researchers reported Dec. 17 in the journal Nature Biotechnology.

The study also showed that two well-known therapies – monoclonal antibodies and the steroid dexamethasone — can help treat COVID-19 infections.

But in the case of the antibodies, treatment is only effective if administered early in the course of the disease. In the case of steroids, it’s only effective if administered during later stages of the disease.

The different immune system responses to the virus as observed in standard laboratory animals and humans have made it difficult for scientists to pinpoint the tipping point between mild and severe cases of COVID-19. But Flavell’s mice engineered to have a human-like immune system offered an opportunity to answer the question.

Researchers genetically modified the murine immune system to make it more human-like. The mice even express human cytokines, growth factors secreted by the liver, and other cells in the body that are essential regulators of stem cell proliferation and maturation. These humanized “MISTRG” mice accept and nourish human cells, especially bone marrow stem cells, without destroying them and allowing them to make mature blood cells.

“If you infect a standard laboratory mouse with SARS-CoV-2, they will get infected, but not get seriously ill,” said Flavell, Sterling Professor of Immunobiology at Yale and senior author of the paper. “But our humanized mice get sick and just don’t get better. Their whole immune system is on fire.”

The research team — which was led by first author Esen Sefik, a Howard Hughes Medical Institute (HHMI) Fellow at the Damon Runyon Cancer Research Foundation have introduced the SARS-CoV-2 virus taken from seriously ill human patients into the nasal passages of their humanized mice and then followed the course of the disease.

They found that the infected mice exhibited the same symptoms as severely ill human patients, such as lung damage, weight loss, and a heightened, persistent inflammatory immune response that damages tissues. They then treated the mice with monoclonal antibodies provided by Michel Nussenzweig, an immunologist at Rockefeller University and, like Flavell, an HHMI investigator. They found that these antibodies, which specifically target the virus, were effective if given before or very early after infection but did little to stifle symptoms if administered in later stages of infections.

Conversely, during the early stages of infection, the immune suppressant dexamethasone was fatal to mice when it suppressed the initial immune response crucial to combat the virus. However, it helped clear infection during later stages of the disease by suppressing the inflammatory response that had begun damaging organs.

“Early in the course of disease, a strong immune response is crucial for survival,” Sefik said. “Later in the disease, it can be fatal.”

The scientists said that the humanized mice models might also reveal strong clues to the causes and potential treatments of so-called long and severe COVID.

Journal Reference

  1. Sefik, E., Israelow, B., Mirza, H. et al. A humanized mouse model of chronic COVID-19. Nat Biotechnol (2021). DOI: 10.1038/s41587-021-01155-4


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