How COVID-19 triggers massive inflammation in the body

Almost two years after the COVID-19 pandemic was declared by the World Health Organization (WHO), experts are still looking for answers to some of the questions posed by the virus.

A study led by researchers at Boston Children's Hospital explains for the first time why the COVID-19 disease causes severe inflammation in some people, with marked acute respiratory distress and multiorgan damage.

Surprisingly, the study also finds that the antibodies that people develop when they get COVID-19 can sometimes cause more inflammation, while the antibodies generated by COVID-19 mRNA vaccines seem not to.

The researchers, led by doctors Judy Lieberman and Caroline Junqueira, from the Boston Children's Program in Cellular and Molecular Medicine, along with Dr. Michael Filbin, at Massachusetts General Hospital, published their findings on April 6 in Nature. “We wanted to understand what distinguishes patients with mild versus severe COVID-19. We know that many inflammatory markers are elevated in people with serious illnesses and that inflammation is at the root of the severity of the disease, but we didn't know what triggers inflammation,” Lieberman said.

The researchers analyzed fresh blood samples from patients with COVID-19 who came to the emergency department at Massachusetts General Hospital. They compared them with samples from healthy people and patients with other respiratory conditions. They also looked at lung autopsy tissue from people who had died from COVID-19.

A fierce 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 suffer a fierce death (called pyroptosis) that releases an explosion of powerful inflammatory warning signals. “In infected patients, about 6 percent of the monocytes in the blood were dying of inflammatory death,” Lieberman says. “That's a great number to find, because the cells that die are quickly eliminated from the body.”

When examining the lung tissue of people who died from COVID-19, they found that about a quarter of the macrophages in the tissue were dying. When researchers studied 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 was a surprise, since monocytes do not have ACE2 receptors, the classic portal of entry of the virus, and macrophages have low amounts of ACE2. Lieberman believes that SARS-CoV-2 infection of monocytes could have previously been missed in part because researchers often study frozen blood samples, in which no dead cells appear.

The study also showed that while SARS-CoV-2 was able to infect monocytes and macrophages, it could not produce new infectious viruses. Researchers believe that the cells died rapidly from pyroptosis before the new viruses could fully form. “Somehow, the uptake of the virus by these 'sentinel' cells is protective: it absorbs the virus and recruits more immune cells. But the bad news is that all these inflammatory molecules are released. In people who are more prone to inflammation, such as the elderly, this can get out of control,” said Lieberman.

Antibodies that facilitate infection?

A certain group of monocytes was especially likely to become infected: those carrying a receptor called CD16. These “non-classic” monocytes make up only about 10 percent of all monocytes, but their number 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 spike protein of SARS-CoV-2. Researchers believe that these antibodies may actually facilitate infection of monocytes that carry the receptor. “Antibodies coat the virus, and cells with the CD16 receptor absorb the virus,” Lieberman says.

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

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

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