Researchers from Yale University’s Richard Flavell’s laboratory have discovered that the reason why between 80 and 90% of people infected with COVID-19 only have mild symptoms, while between 10 and 20% have more serious or life-threatening symptoms, may lie in the antiviral inflammatory response of each patient’s body.

The researchers used laboratory mice with immune systems that were similar to those of humans for their research, and their findings from these “humanized mice” revealed that the causes of severe COVID may be related to our own antiviral inflammatory response to the virus, as reported in the journal ‘Nature Biotechnology.’

The study also found that monoclonal antibodies and the steroid dexamethasone, both well-known treatments, can effectively treat COVID-19 infections.

In the case of antibodies, however, treatment is only beneficial if it is administered early in the disease’s progression. In the case of steroids, they are only useful if given at the end of the disease’s progression.

Since conventional laboratory animals and humans have exhibited distinct immune system responses to the virus, scientists have had difficulty determining the tipping point between mild and severe COVID-19 cases. Flavell’s mice, which have an immune system that is similar to that of humans, provide a way to address the question.

“If you infect a standard laboratory mouse with SARS-CoV-2 they will get infected, but not get seriously ill,” says Flavell, Sterling Professor of Immunobiology at Yale and lead author of the work.

“But our humanized mice get sick and just don’t get better. Their whole immune system is on fire.”

The researchers, led by first author Esen Sefik, a Howard Hughes Medical Institute (HHMI) scholar at the Damon Runyon Cancer Research Foundation, injected the SARS-CoV-2 virus into the nostrils of his humanized mice and then monitored the disease’s progression.

The infected mice showed the same symptoms as extremely ill human patients, including lung damage, weight loss, and a prolonged and increased inflammatory immune response that damages tissues, according to the researchers.

They next used monoclonal antibodies given by Michel Nussenzweig, an immunologist at Rockefeller University and an HHMI researcher like Flavell. They discovered that these antibodies, which target the virus specifically, were beneficial if given before or very soon after infection, but did nothing to alleviate symptoms if given later in infections.

The immunosuppressant dexamethasone, on the other hand, was lethal to mice during the early stages of infection by reducing the initial immune response, which is critical for battling the virus. During the later stages of the sickness, however, it helped clear the infection by decreasing the inflammatory response that had begun to harm organs.

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

According to scientists, humanized mouse models could give important information regarding the origins and treatments for COVID, a chronic and severe disease.

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