Severe COVID-19 disease is known to be linked to increased inflammation. However, how SARS-CoV-2 triggers that inflammation is not understood. Now, researchers show, for the first time, how COVID-19 causes severe inflammation in some people, leading to acute respiratory distress and multi-organ damage.

The study found that SARS-CoV-2 can infect monocytes and macrophages. Once infected, both types of immune cells die via pyroptosis and release an explosion of inflammatory alarm signals. Surprisingly, the study also found that antibodies developed by people with COVID-19 can sometimes lead to more inflammation, while antibodies generated by mRNA COVID-19 vaccines seem not to.

This work is published in Nature, in the article, “FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation.

The investigators analyzed fresh blood samples from patients with COVID-19 in the emergency department at Massachusetts General Hospital in Boston. They compared these 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.

“We wanted to understand what distinguishes patients with mild versus severe COVID-19,” said Judy Lieberman, MD, PhD, professor of pediatrics at Harvard Medical School. “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 hadn’t known what triggers the inflammation.”

They found that SARS-CoV-2 can infect monocytes (immune cells in the blood) as well as macrophages (in the lungs). Both monoctyes and macrophages, the authors explained, are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D. This leads to inflammatory deaths, known as pyroptosis, and the release of potent inflammatory mediators.

The researchers uncovered that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. “In the infected patients, about 6% of blood monocytes were dying an inflammatory death,” said Lieberman. “That’s a large number to find, because dying cells are rapidly eliminated from the body.”

Examining the lung tissue from people who 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 about 10% of monocytes and 8% of lung macrophages were infected.

The fact that monocyte and macrophages can be infected with SARS-CoV-2 was a surprise, since monocytes don’t carry ACE2 receptors, the classic entry portal for the virus, and macrophages have low amounts of ACE2. Lieberman thinks SARS-CoV-2 infection of monocytes might have previously been missed in part because researchers often study frozen blood samples, in which dead cells do not show up.

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

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

A certain group of monocytes was especially likely to be infected—those carrying the CD16 receptor. These “non-classical” monocytes make up only about 10% of all monocytes, but their numbers were increased in patients with COVID-19. They were also more likely to be infected—about half were infected, as compared with none of the classical blood monocytes.

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

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 suggest that vaccine-generated antibodies have slightly different properties than antibodies that develop during infection and don’t bind as well to the CD16 receptor. As a result, the cells don’t take the virus up.

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

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