Study reveals how Covid-19 infections can set off massive inflammation in the body – CNN

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From the early days of the pandemic, doctors noticed that in severe cases of Covid-19 the ones that landed people in the hospital on ventilators with shredded lungs most of the internal wreckage wasnt being directly inflicted by the virus itself but by a blizzard of immune reactions triggered by the body to fight the infection.

Researchers knew that these so-called cytokine storms were damaging, but they didnt know why the SARS-CoV-2 virus seemed to be so good at setting them off.

A new study published Wednesday in the journal Nature is helping to explain how these immune overreactions happen to Covid-19 patients.

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

Monocytes and macrophages are white blood cells, and they are frontline workers of the immune system. Their job is to circulate in the blood and tissues, to find and destroy pathogens. They do this by eating or really, surrounding and absorbing threats like viruses to keep them from being able to infect other cells.

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

In the case of the SARS-CoV-2 virus, however, that doesnt happen. The virus gets out of the endosome and escapes into the body of the cell, where it starts making copies of itself.

The viruses not only get taken up, but once they get taken up, the virus starts replicating, so that was surprising, said Dr. Judith Lieberman, a pediatric immunologist at Boston Childrens Hospital, who led the research.

A virus starting to make copies of itself in the body is never a good thing, but when this happens to these protector cells, it sets off a next-level set of alarms.

These alarms, in turn, summon agents called inflammasomes that, in essence, respond by burning it all down. They help the infected cell die by pyroptosis, or fiery death.

Pyroptosis is a newly recognized phenomenon. It happens in other diseases, too, like sepsis.

When cells die by pyroptosis, they release all kinds of inflammatory proteins that cause fever and summon more immune cells to the site, Lieberman said. It sets off a cascade of crisis signals thats very difficult to stop.

We dont have any way of treating that once it gets started. Its just sort of its like a little fire. It spreads and explodes and no fire extinguisher is capable of putting it out, she said.

I think its really elegant, said Donna Farber, a professor of microbiology and immunology at Columbia University, describing the study. They actually put some pieces together that hadnt been put together before. She was not involved in the research.

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

All the patients we studied had signs of respiratory distress and pneumonia. The ones who had [SARS-CoV-2] had many more of these inflammasomes and dying cells, Lieberman said. So its likely that [SARS-CoV-2] is particularly good at inducing it, but we dont know why.

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

Theyre much, much more likely to start these inflammatory fires, she said. They have sort of a low slow burn going on anyway. And once it gets started its really hard to put out the fire.

Theres another piece of the process, though, that suggests a way it might be stopped, and thats how the virus gets into these white blood cells.

Monocytes and macrophages lack ACE-2 receptors, the doors that the virus uses to dock onto and infect other kinds of cells. Instead, the virus enters these cells because of another immune system helper the Y-shaped antibodies that grab onto the virus in an attempt to block it from docking onto our cells.

When antibodies grab viruses, the tail of the antibody called the FC portion sticks out. That stalk acts a flag to wave down monocytes and macrophages to let them know theres a bad guy to pick up.

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

Those antibodies connect to monocytes with CD16 receptors, triggering the cell to absorb the virus. Once inside, the virus starts trying to copy itself, setting off the damaging inflammatory reaction.

John Wherry, director of the Institute for Immunology at the University of Pennsylvanias Perelman School of Medicine, said thats something weve been wondering about with Covid-19 infections, whether there might be some kind of antibody enhancement of disease. Wherry was not involved in the study.

He said this can happen with other infections, too, like dengue fever. The more times a person gets infected with the dengue virus, the sicker they get with each subsequent bout. Thats the opposite of whats supposed to happen. A person who recovers from an infection usually has better protection against future ones.

Wherry said theres no evidence that the antibodies facilitating these severe inflammatory reactions come from prior infections or from other kinds of coronaviruses. He said antibodies are made quickly in infections and that the ones at work here were probably made in response to the persons current illness. In that way, its different than what happens with dengue.

However, the antibodies generated by vaccines dont seem to facilitate monocyte infections and the inflammatory cascades that follow. They tested that in the study.

I think what was interesting about this is it could provide a clue and perhaps even some druggable targets for why some of the inflammation that we see in severe Covid patients might get kick started the wrong way or proceed out of control, Wherry said. So thats where I think this is quite interesting.

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Study reveals how Covid-19 infections can set off massive inflammation in the body - CNN