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A study published in “Nature” led by researchers at Boston Children’s Hospital (USA) 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 that people develop when they contract Covid-19 can sometimes cause more inflammation, while those generated by mRNA vaccines against Covid-19 appear not to.
“We wanted to understand what distinguishes patients with mild from severe Covid-19,” says Judy Lieberman, author of the study. “We know that many inflammatory markers are elevated in people with severe disease and that inflammation is at the root of disease severity, but we don’t know what triggers inflammation.”
The researchers analyzed blood samples from Covid-19 patients 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.
They discovered 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 types of cells undergo a ferocious death (called pyroptosis) that releases a burst of powerful inflammatory alarm signals.
“In the infected patients, about 6% of the monocytes in the blood were dying an inflammatory death,” explains Lieberman. That’s a big number to find, because cells that die are quickly eliminated from the body.”
Examining lung tissue from people who have died from Covid-19, they found that about a quarter of the macrophages in the tissue were dying.
When the researchers studied the cells for signs of SARS-CoV-2, they found that around 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 for the virus, and macrophages have low amounts of ACE2.
Lieberman thinks SARS-CoV-2 infection of monocytes may have been previously 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 was unable to produce new infectious viruses. The researchers believe that the cells died rapidly by pyroptosis before the new viruses could fully form.
“In some way, the uptake of the virus by these ‘sentinel’ cells is protective: it takes up the virus and recruits more immune cells,” Lieberman clarifies. “But the bad news is that all these inflammatory molecules are released. In people who are more prone to inflammation, like the elderly, this can get out of hand.”
But a certain group of monocytes was especially likely to be infected: those that carried a receptor called CD16. These “non-classical” monocytes make up only about 10% of all monocytes, but their number increased in Covid-19 patients. 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. The researchers believe that these antibodies may actually facilitate the infection of monocytes that carry the receptor. “The antibodies coat the virus, and cells with the CD16 receptor take up the virus,” says Lieberman.
However, when healthy patients who had received mRNA vaccines against Covid-19 were studied, the antibodies they developed did not appear to facilitate infection. The reason for this is not clear; 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 as well to the CD16 receptor. As a result, the cells do not absorb the virus.
The researchers believe these findings may have implications for the use of monoclonal antibodies to treat Covid-19, helping to explain why the treatment works only when given early. “It may be that later on, the antibodies help to improve inflammation,” he says. We may need to look at the properties of the antibodies.”
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