Two new studies revealed why COVID-19 causes severe inflammation in some patients

Immune cells infected with SARS-CoV-2 may trigger a massive inflammatory response that contributes to the severity of COVID-19, suggest two articles, one published today in the scientific journal Nature and a preliminary version published online at the beginning of this month.

Since the early days of the pandemic, research has suggested that inflammation leads to significant respiratory distress and other organ damage, characteristic of severe COVID. But scientists have been striving to identify what triggers inflammation.

The latest studies involve two types of white blood cells: macrophages in the lungs and monocytes in the blood that, once infected with the virus, trigger inflammation. The studies also provide conclusive evidence that the virus can infect and replicate in immune cells, and reveal how it enters those cells. The evidence of such infections has been mixed so far.

“The studies offer a plausible explanation of the seriousness of the progress of COVID-19,” explains Malik Peiris, a virologist at the University of Hong Kong. He adds: “I don't think it's the only or the most important path, but it's certainly interesting.” Still, for Jian Zheng, an immunologist at the University of Iowa in Iowa City, “infected immune cells could offer a potential target for drug development.”

Hyperactive response

In the Nature article, Judy Lieberman, immunologist at Boston Children's Hospital in Massachusetts, and her colleagues analyzed blood samples from people with COVID-19 and found that about 6% of monocytes, cells “Early Response” immune systems that patrol the body in search of foreign invaders, were experiencing a type of cell death associated with inflammation, known as pyroptosis. “Seeing that many cells die is unusual,” he warns, “because the body usually gets rid of dead cells quickly.”

When researchers looked at the dying cells, they found that they were infected with SARS-CoV-2. They suggest that the virus was probably activating inflammasomes, large molecules that trigger a cascade of inflammatory responses that ended in cell death.

Scientists also observed another type of immune cell, macrophages, in the lungs of people who had died of COVID-19. Because macrophages collect cellular waste, including viral waste, it was a difficult task to show whether macrophages were infected with SARS-CoV-2 or simply absorbed these wastes. The team found that about a quarter of macrophages had activated inflammasomes and a fraction of them had been infected with the virus. Other infected lung cells, the epithelium, did not show the same response.

The results align with those of the second study, published in BioRXIV and not yet peer-reviewed, by Esen Sefik, immunologist at Yale University School of Medicine, New Haven, and his colleagues. They also found that the virus could infect and replicate in macrophages in human lung cells and in a mouse model of the human immune system. Macrophages showed the same inflammatory response described by Lieberman and eventually died.

The team also found that giving mice drugs that blocked inflammasomes prevented severe respiratory distress. The drugs “rescued the mice so that they were not so sick,” says Sefik. This suggests that infected macrophages play a role in pneumonia seen in people with severe COVID-19.

“The inflammatory response of macrophages could be their way of stopping the replication of SARS-CoV-2,” underlines study co-author Richard Flavell, immunologist, also from Yale, and the Howard Hughes Medical Institute. When the inflammasomes were activated, the virus stopped replicating in the cells. But when researchers blocked inflammasomes, macrophages began to produce infectious viral particles. That is a “surprising” finding, Peiris points out, because it shows that macrophages can help the infection.

But Stanley Perlman, a virologist also at the University of Iowa, says follow-up studies will be needed to determine how important infected immune cells are in inducing severe COVID-19 compared to other possible mechanisms.

Viral entry

Both teams were also able to show how SARS-CoV-2 can enter immune cells. Researchers are puzzled by this because cells don't have many ACE2 receptors, the main entry point of the virus.

In experiments with human and mouse cells, Sefik and Flavell discovered that SARS-CoV-2 could enter lung macrophages through the limited number of ACE2 receptors present. But the virus also broke through another surface protein, known as the Fcγ receptor, with the help of antibodies. When the virus found antibodies attached to the Fcy receptor, instead of inactivating the virus, it was collected in the cell.

Lieberman says that this is also how the virus enters monocytes, which do not have ACE2 receptors. Only monocytes with the Fcγ receptor could be infected. But the expert assures that not all antibodies facilitate viral entry. The team found that antibodies produced by people who received the mRNA vaccine developed by Pfizer and BioNTech did not allow monocytes to absorb the virus.

That finding is reassuring, given that many people have been vaccinated with mRNA vaccines, according to Peiris. But more studies are needed to understand which types of antibodies facilitate viral uptake by monocytes and whether vaccines using other technologies could induce a different response.

KEEP READING: