How COVID-19 triggers massive inflammation

A study by researchers at Boston Children’s Hospital explains for the first time why COVID-19 causes severe inflammation in some people, leading to acute respiratory distress and multi-organ damage. Surprisingly, the study also finds that the antibodies people develop when they get COVID-19 can sometimes lead to more inflammation, whereas the antibodies generated by COVID-19 mRNA vaccines don’t seem to.

The researchers, led by Judy Lieberman, MD, Ph.D. and Caroline Junqueira, Ph.D. in the Boston Children’s Program in Cellular and Molecular Medicine, with Michael Filbin, MD, at Massachusetts General Hospital, released their findings on 6 april in Nature.

“We wanted to understand what distinguishes patients with mild or severe COVID-19,” says Lieberman. “We know that many inflammatory markers are elevated in people with severe disease and that inflammation drives disease severity, but we didn’t know what triggers inflammation. »

Investigators analyzed fresh blood samples from patients with COVID-19 presenting to the emergency room at Massachusetts General Hospital. They compared them to samples from healthy people and patients with other respiratory conditions. They also examined lung autopsy tissue from people who died of COVID-19.

A fiery death of immune cells

They found that SARS-CoV-2 can infect monocytes — immune cells in the blood that act as “sentinels” or early responders to infection — as well as macrophages, similar immune cells in the lungs. Once infected, both cell types die a fiery death (called pyroptosis) that releases a burst of powerful inflammatory warning signals.

“In infected patients, about 6% of blood monocytes died an inflammatory death,” says Lieberman. “That’s a big number to find, because dying cells are quickly cleared from the body. »

By examining the lung tissue of people who died from COVID-19, they found that about a quarter of the macrophages in the tissue died.

When the researchers studied the cells for signs of SARS-CoV-2, they found that about 10% of monocytes and 8% of lung macrophages were infected.

The fact that monocytes and macrophages can be infected with SARS-CoV-2 came as a surprise, as monocytes do not carry ACE2 receptors, the virus’ classic entry gate, and macrophages have low amounts of ACE2 receptors. ‘ACE2. Lieberman thinks the SARS-CoV-2 infection of monocytes could have been missed in part because researchers often study frozen blood samples, in which dead cells do not appear.

The study also showed that while SARS-CoV-2 was able to infect monocytes and macrophages, it was not able to produce new infectious viruses. The researchers believe the cells died rapidly from pyroptosis before new viruses could fully form.

“In some ways, the uptake of the virus by these ‘sentinel’ cells is protective: it takes up the virus and recruits more immune cells,” says Lieberman. “But the bad news is that all of these inflammatory molecules are released. In people who are more prone to inflammation, like the elderly, it can get out of control. »

Antibodies facilitating infection?

A certain group of monocytes was particularly susceptible to infection: those carrying a receptor called CD16. These “non-classical” monocytes make up only about 10% of all monocytes, but their numbers have increased in patients with COVID-19, the researchers found. They were also more likely to be infected: about half were infected, compared to none of the classic blood monocytes.

The CD16 receptor appears to recognize antibodies against the SARS-CoV-2 spike protein. The researchers believe that these antibodies may actually facilitate the infection of monocytes carrying the receptor. “The antibodies coat the virus, and the cells with the CD16 receptor then take up the virus,” says Lieberman.

However, when the team studied healthy patients who had received mRNA vaccines against COVID-19, the antibodies they developed did not appear to facilitate infection. The reason for this is still unclear; the researchers believe that the antibodies generated by the vaccine have slightly different properties than the antibodies that develop during infection and do not bind to the CD16 receptor as well. As a result, the cells do not take up the virus.

Lieberman and his colleagues believe these findings may have implications for the use of monoclonal antibodies to treat COVID-19, helping to explain why the treatment only works when given early. “It may be that later on the antibodies can help boost the inflammation,” she says. “We may need to look at the properties of antibodies. »


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