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Covid-19 infections can trigger massive inflammation in the body

Researchers knew these so-called cytokine storms were damaging, but they didn’t know why the SARS-CoV-2 virus seemed so good at triggering them.

The study found that the SARS-CoV-2 virus can infect certain types of immune cells called monocytes and macrophages.

Monocytes and macrophages are white blood cells and are front line workers of the immune system. Their job is to circulate in the blood and tissues, finding and destroying pathogens. They do this by eating – or really, surrounding and absorbing – threats like viruses to prevent them from infecting other cells.

Once a bad actor is absorbed, these cells have what can be described as a cellular garbage can, called an endosome, which normally shuts down the infectious agent.

In the case of the SARS-CoV-2 virus, however, this does not occur. The virus exits the endosome and escapes into the cell body, where it begins to reproduce.

“Not only are the viruses absorbed, but once they are absorbed, the virus begins to replicate, which was surprising,” said Dr. Judith Lieberman, a pediatric immunologist at Boston Children’s Hospital, who led the research.

A virus starting to replicate in the body is never a good thing, but when it happens to those protective cells, it sets off a series of higher level alarms.

A fiery death

These alarms, in turn, summon agents called inflammasomes which, essentially, respond by burning everything. They help the infected cell to die by pyroptosis, or “fiery death”.

Pyroptosis is a newly recognized phenomenon. It also occurs in other diseases, such as sepsis.

Covid-19 infections can trigger massive inflammation in the body

“When cells die from pyroptosis, they release all sorts of inflammatory proteins that cause fever and summon more immune cells to the site,” Lieberman said. It triggers a cascade of crisis signals that are very difficult to stop.

“We have no way to deal with this once it starts. It’s like a small fire. It spreads and explodes and no extinguisher is able to put it out,” she said .

“I think it’s really elegant,” said Donna Farber, professor of microbiology and immunology at Columbia University, describing the study. “They actually put pieces together that hadn’t been put together before.” She did not participate in the research.

By comparing blood cells from healthy people to those from people who came to hospital with Covid-19 and blood from people with pneumonia from other causes, researchers found that this process seems to happen more often. with Covid-19.

Covid-19 infections can trigger massive inflammation in the body

“All the patients we studied had signs of respiratory distress and pneumonia. Those who had [SARS-CoV-2] had a lot more of these inflammasomes and dying cells,” Lieberman said. “So it is likely that [SARS-CoV-2] is particularly good at inducing it, but we don’t know why.”

Lieberman said the study also helps explain why people who are older or have underlying health conditions like obesity or diabetes have higher risks of serious outcomes with Covid-19. These conditions are already associated with some level of inflammation in the body.

“They’re much, much more likely to start these inflammatory fires,” she said. “They kind of have a slow, slow burn anyway. And once it’s started, it’s really hard to put the fire out.”

The role of antibodies

There is another element to the process, however, that suggests a way to stop it, and that is how the virus gets into those white blood cells.

Monocytes and macrophages lack ACE-2 receptors, the gates the virus uses to dock and infect other cell types. Instead, the virus enters these cells because of another helper of the immune system – the Y-shaped antibodies that latch onto the virus to try to prevent it from attaching to our cells.

Covid-19 infections can trigger massive inflammation in the body

When antibodies catch viruses, the tail of the antibody – called the FC part – sticks out. This rod acts as a flag to wave monocytes and macrophages to let them know there’s a bad guy out there to pick up.

Not all monocytes recognize the same antibodies. The study found that people with Covid-19 tended to have more than one unusual type of monocytes that had CD16 receptors. These receptors recognize the antibody stalks the body makes to fight the SARS-CoV-2 virus.

These antibodies connect to monocytes with CD16 receptors, causing the cell to take up the virus. Once inside, the virus begins to try to copy itself, triggering the damaging inflammatory response.

John Wherry, director of the Institute of Immunology at the Perelman School of Medicine at the University of Pennsylvania, said it’s something we’ve wondered with Covid-19 infections, if there might be have some sort of disease antibody enhancement. Wherry did not participate in the study.

He said it could also happen with other infections, such as dengue fever. The longer a person is infected with the dengue virus, the sicker they become with each subsequent episode. This is the opposite of what is supposed to happen. A person recovering from an infection is usually better protected against future infections.

Drugged targets

Wherry said there is no evidence that the antibodies facilitating these severe inflammatory reactions come from previous infections or from other types of coronavirus. He said antibodies are made quickly in infections and those at work here were likely made in response to the person’s current illness. In that way, it’s different from what happens with dengue fever.

However, vaccine-generated antibodies do not appear to facilitate monocyte infections and subsequent inflammatory cascades. They tested this in the study.

“I think what was interesting about that was that it might provide a clue and maybe even drug targets as to why some of the inflammation that we see in severe Covid patients might start from the wrong way or get out of hand,” Wherry said. “So that’s where I think it’s quite interesting.”

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