A study led by researchers at Harvard Medical School and Boston Children’s Hospital explains for the first time why COVID-19 causes severe inflammation in some people, leading to acute respiratory distress and multi-organ damage.
Image credit: Annett Klingner via Pixabay, free license
Surprisingly, the study also finds that antibodies that people develop when they contract COVID-19 sometimes lead to more inflammation, while antibodies generated by mRNA COVID-19 vaccines seem not to.
Findings were published in Nature. The team was led by Judy Lieberman, HMS professor of paediatrics at Boston Children’s; Caroline Junqueira, HMS research associate in paediatrics at Boston Children’s; and Michael Filbin, HMS assistant professor of emergency medicine at Massachusetts General Hospital.
“We wanted to understand what distinguishes patients with mild versus severe COVID-19,” said Lieberman. “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.”
Fiery death of immune cells
The investigators analyzed fresh blood samples from patients with COVID-19 coming to the emergency department at Mass General. 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.
They found that SARS-CoV-2 can infect monocytes—immune cells in the blood that act as sentinels or early responders to infection—and macrophages, similar immune cells in the lungs.
Once infected, the team found that both types of cells die a fiery death called pyroptosis that releases an explosion of powerful inflammatory alarm signals.
“In the infected patients, about 6 per cent 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 was dying.
When the researchers studied the cells for signs of SARS-CoV-2, they found that about 10 per cent of monocytes and 8 per cent of lung macrophages were infected.
The fact that monocytes 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 because researchers often study frozen blood samples, in which dead cells do not show up.
The study also showed that while SARS-CoV-2 could infect monocytes and macrophages, it could not 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. This can get out of control in people who are more prone to inflammation, such as the elderly.”
Antibody facilitators?
The team found that a particular group of monocytes was especially likely to be infected: those carrying a receptor called CD16. The researchers found that these “non-classical” monocytes make up only about 10 per cent of all monocytes, but their numbers were increased in patients with COVID-19. Almost half were infected, compared with none of the classical blood monocytes.
The CD16 receptor appears to recognize antibodies against the SARS-CoV-2 spike protein. The researchers believe these antibodies may facilitate the 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, namely the Moderna and Pfizer vaccines, the antibodies they developed did not facilitate infection.
The reason for this is still unclear. The researchers believe that vaccine-generated antibodies have slightly different properties from 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.
The 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 antibodies may help enhance inflammation later on,” said Lieberman. “We may need to look at the properties of the antibodies.”
Source: HMS