What causes COVID-19?

Originally written by Smriti Mallapaty

Studies have shown that infected immune cells induce large-scale inflammatory responses.

According to a paper published april 6 in Nature and a preprint paper published online on April 1, immune cells infected with the new coronavirus (SARS-CoV-2) can trigger a massive inflammatory response that can lead to severe COVID-19.

Since the beginning of the outbreak, studies have shown that inflammation can lead to severe respiratory distress and other organ damage, which are all signs of severe COVID-19. But scientists have struggled to determine what causes these inflammations.

The coronavirus can enter the immune cells of the lungs, macrophages (pictured), inducing an inflammatory response. | Steve Gschmeissner/Science Photo Library

The two newest studies point the cause to two classes of white blood cells — macrophages in the lungs and monocytes in the blood — that induce inflammation when infected with the new coronavirus. The two studies also used conclusive evidence that the new crown virus can infect and replicate immune cells, while revealing how the new crown virus enters these cells. Until then, the evidence for this type of infection has been inconsistent.

Two studies have given a plausible explanation for the course of severe COVID-19, with Malik Peiris, a virologist at the University of Hong Kong, saying, "I don't think it's the only or most important pathway, but it's certainly an interesting one." ”

Either way, infected immune cells could be a potential target for drug discovery, says Jian Zheng, an immunologist at the University of Iowa.

Over-responding

In the paper published in Nature[1], Judy Lieberman, an immunologist at Boston Children's Hospital, and her colleagues analyzed blood samples from people infected with COVID-19. They found that about 6 percent of monocytes — immune cells known as "early responders" who search the whole body for foreign invaders — developed a type of cell death associated with inflammation, known as pyroptosis. It's not normal to see so many dead cells, she said, because the body is generally able to quickly clear dead cells.

While studying these dying cells, the researchers found that they were all infected with the new coronavirus. They believe that the new crown virus is likely to activate the small body of inflammation , a class of large molecules that can induce an inflammatory response that ultimately leads to cell death.

The research team also analyzed macrophages, another type of immune cell in the lungs of patients who died from COVID-19. Because macrophages collect cellular waste, including viral debris, researchers have had a hard time telling whether macrophages are infected with the new coronavirus or just phagocytosis. The team found that about 1/4 of macrophages activated the inflammasome, and a small percentage of macrophages were indeed infected with the new crown virus. Other infected lung cells, such as epithelial cells, did not have the same response.

These results are consistent with the results of the second study [2]. The second study, published on a bioRxiv preprint server by Esen Sefik, an immunologist at Yale University School of Medicine, and her colleagues has not been peer-reviewed. They also found in human lung cells and mouse models of the human immune system that the new coronavirus can infect macrophages and replicate in them. These macrophages developed the same inflammatory response as Lieberman described and eventually died.

The team also found that giving mice drugs that block inflammasomes prevented severe respiratory distress. Sefik said the drugs "saved the lives of the mice so they didn't get too sick." "This shows that infected macrophages play a role in pneumonia in severely ill COVID-19 patients."

The inflammatory response of these macrophages may be the way they use to stop the coronavirus from replicating, said study co-author Richard Flavell, an immunologist at Yale University and the Howard Hughes Medical Institute. After the inflammasome is activated, the new coronavirus stops replicating within the cell. But if the researchers block the inflammasome, macrophages begin to produce infectious viral particles.

The results were "surprising," Pei said, because it showed that macrophages can assist in infection.

But Stanley Perlman, a virologist at the University of Iowa, believes that follow-up studies are still needed to compare the importance of infected immune cells in inducing severe COVID-19 with other possible mechanisms.

Virus intrusion

The two teams also revealed how the coronavirus enters immune cells. Researchers have been puzzled by this because these immune cells do not carry a large number of ACE2 receptors, which are the main point of entry for the new crown virus.

In experiments on human and mouse cells, Sefik and Flavell found that the new coronavirus can enter lung macrophages through these limited numbers of ACE2 receptors. With the help of antibodies, the new crown virus can also invade through another surface protein, which is the Fcγ receptor. When the new crown virus encounters antibodies on the Fcγ receptor, the new crown virus does not lose its activity, but is swallowed into the cell.

This is also how the new coronavirus enters monocytes, which do not have ACE2 receptors, Lieberman said. Only monocytes with Fcγ receptors can be infected.

But Lieberman says not all antibodies can help the virus invade. Their team found that antibodies produced by mRNA vaccinators at Pfizer and BioNTech were unable to help mononuclear cells engulf the coronavirus.

This result is reassuring because there are so many people who have already been vaccinated against mRNA, Pei weiss said. But more research is needed to understand which antibodies can promote monocyte swallowing of the virus, and whether other routes of vaccines induce another response.

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What triggers severe COVID? Infected immune cells hold clues were published as a headline in the news section of Nature on April 6, 2022

This article is reproduced from Nature Portfolio (ID:nature-portfolio) with permission, please contact the original author for secondary reprinting.