Severe COVID-19: Could new findings lead to better prevention?

• Most infections with SARS-CoV-2 occur through the nose and throat and result in major changes to the epithelial cells, the cells forming the tissue that lines the outer layer of organs, blood vessels, and other parts of the body.
• The immune response in this area is key to the severity of the illness.
• In severe COVID-19, immune responses are markedly reduced, but inflammatory responses are increased.
• Focusing on preventive or early therapeutic interventions in the nose and throat may enhance the antiviral response and prevent severe disease.

A new study, to appear in the journal Cell, suggests that the first response to SARS-CoV-2 infection in the nose and throat may determine the severity of the illness.

A team from Boston Children’s Hospital, the Massachusetts Institute of Technology, and the University of Mississippi Medical Center looked at cells from the nose and throat of people with SARS-CoV-2 infections and compared these with the samples from healthy individuals who formed the control group.

Cell changes

The researchers took nasal swabs from 35 adults with COVID-19 between April and September 2020.

They then sequenced the RNA in each cell to see which cells contained RNA from the virus — showing they were infected — and which of the cell’s genes were turned on or off in response.

The researchers found that more of the genes that respond to infection were turned on in infected cells compared with healthy cells. However, the effect on the cells with SARS-CoV-2 was different in people with severe and mild infections.

Those people with COVID-19 had more mucus-secreting cells and far fewer mature ciliated cells — the cells that move foreign material from the airways — than their healthy counterparts. At the same time, they had more immature ciliated cells, which may have been in compensation for the loss of mature ciliated cells.

Of the 58 study participants, 35 had COVID-19, ranging from people with mild symptoms to the critically ill. The study included a control group of 15 healthy people — two of whom had previously had COVID-19 — and six intensive care patients, all of whom had tested negative for SARS-CoV-2 infections.

“Why some people get more sick than others has been one of the most puzzling aspects of this virus from the beginning,” says Dr. José Ordovás-Montañés of Boston Children’s Hospital, co-senior investigator on the study.

Increased inflammation

Although the study had only a small sample size, there were some interesting results that may help in the development of effective treatments.

The researchers found that in those with mild symptoms, the genes involved in antiviral responses were switched on. In those with severe symptoms, this interferon response, which kick-starts the immune response, was decreased, but the inflammatory response was increased.

Speaking to Medical News Today, Dr. Christopher Coleman, assistant professor of infection immunology at the University of Nottingham in the United Kingdom, commented: “The finding about the different immune response is especially interesting. Coronaviruses have numerous proteins that block innate immunity, including interferon, so the low response may be due to high viral protein expression.”

Some researchers think that it is extreme inflammatory responses that are responsible for the more severe symptoms of COVID-19.

Enhancing the antiviral response

“Everyone with severe COVID-19 had a blunted interferon response early on in their epithelial cells and were never able to ramp up a defense,” says Dr. Ordovás-Montañés. “Having the right amount of interferon at the right time could be at the crux of dealing with SARS-CoV-2 and other viruses.”

“This study is consistent with previous studies that have shown that a lack of good interferon response leads to more severe disease,” Dr. Jonathan Stoye, a virologist at the Francis Crick Institute in London, U.K., told MNT. “We need to discover why some people have a good interferon response and others don’t.”

“Focusing on the nasopharynx is key, as that’s where the infection starts. For me, the next step would be to look at whether these findings could be used to come up with a diagnostic test to predict whether people will develop severe COVID-19.”

– Dr. Jonathan Stoye

The researchers now plan to investigate what is causing this difference in the interferon response and whether there are ways to enhance it in early COVID-19 infections, perhaps with a nasal spray or drops. Successful developments might also be useful for other viral infections, such as flu.

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