Immune cells infected with SARS-CoV-2 may trigger a massive inflammatory response that contributes to severe COVID-19, suggest two papers – one published today in Natureand a preprint posted online on April 1st.
Since the pandemic’s early days, research has shown that inflammation leads to significant respiratory distress and other organ damage, hallmarks of severe COVID-19. But scientists have struggled to pinpoint exactly what triggers the inflammation.
The latest studies implicate two types of white blood cells — macrophages in the lungs and monocytes in the blood — that, once infected with the virus, trigger the inflammation. The studies also provide conclusive evidence that the virus can infect and replicate immune cells – and show how it enters those cells. Evidence of such infections has been mixed so far.
The studies offer a plausible explanation for the severe course of COVID-19, says Malik Peiris, a virologist at the University of Hong Kong. “I don’t think it’s the only or the most important way, but it’s certainly interesting.”
Still, infected immune cells could be a potential target for drug development, says Jian Zheng, an immunologist at the University of Iowa in Iowa City.
In which Nature paper1, Judy Lieberman, an immunologist at Boston Children’s Hospital in Massachusetts, and her colleagues examined blood samples from people with COVID-19. They found that about 6% of monocytes – “early responder” immune cells that patrol the body for foreign invaders – underwent a type of cell death associated with inflammation known as pyroptosis. Seeing a lot of cells dying is unusual, she says, because the body normally gets rid of dead cells quickly.
When the researchers looked at the dying cells, they found they were infected with SARS-CoV-2. They suspect the virus likely activated inflammasomes, large molecules that trigger a cascade of inflammatory responses that ended in cell death.
The researchers also looked at another type of immune cell, macrophage, in the lungs of people who had died from COVID-19. Because macrophages collect cellular debris, including viral debris, it was difficult to show whether macrophages were infected with SARS-CoV-2 or just sucking up this debris. The team found that about a quarter of the macrophages had activated inflammasomes, and a fraction of those were actually infected with the virus. Other infected lung cells, epithelial cells, did not show the same response.
The results are consistent with those of the second study published on bioRxiv2 and has yet to be reviewed by Esen Sefik, an immunologist at Yale University School of Medicine, New Haven, and her colleagues. They also found that the virus could infect and replicate macrophages in human lung cells and in a mouse model of the human immune system. The macrophages displayed the same inflammatory response described by Lieberman and eventually died.
The team also found that giving drugs that blocked inflammasomes prevented severe shortness of breath. The drugs “saved the mice so they weren’t as sick anymore,” says Sefik. This suggests that infected macrophages play a role in the pneumonia seen in people with severe COVID-19.
The macrophages’ inflammatory response could be their way of stopping SARS-CoV-2 from replicating, says study co-author Richard Flavell, an immunologist also at Yale and the Howard Hughes Medical Institute. When inflammasomes were activated, the virus stopped replicating in the cells. But when the researchers blocked inflammasomes, the macrophages began producing infectious virus particles.
This is a “stunning” finding, says Peiris, because it shows that macrophages can support infections.
However, Stanley Perlman, a virologist also at the University of Iowa, says follow-up studies will be needed to find out how important infected immune cells are compared to other possible mechanisms for inducing severe COVID-19.
Both teams were also able to show how SARS-CoV-2 can penetrate immune cells. The researchers were puzzled because the cells don’t carry many ACE2 receptors, the virus’s main entry point.
In experiments with human and mouse cells, Sefik and Flavell found that SARS-CoV-2 could enter lung macrophages through the limited number of ACE2 receptors present. But the virus also sneaked in with the help of antibodies through another surface protein known as the Fcγ receptor. When the virus encountered antibodies bound to the Fcy receptor, the virus was not deactivated but taken up into the cell.
Lieberman says this is how the virus enters monocytes that don’t have ACE2 receptors. Only monocytes with the Fcγ receptor could be infected.
But Lieberman says not all antibodies facilitate virus entry. The team found that antibodies produced by people receiving the mRNA vaccine developed by Pfizer and BioNTech failed to allow monocytes to take up the virus.
This finding is reassuring given that many people have been vaccinated with mRNA vaccines, Peiris says. However, more studies are needed to understand what types of antibodies facilitate viral uptake by monocytes and whether vaccines using other technologies might elicit a different response.