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 wasn’t 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 didn’t 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 doesn’t 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 Children’s 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 that’s very difficult to stop.

“We don’t have any way of treating that once it gets started. It’s just sort of it’s like a little fire. It spreads and explodes and no fire extinguisher is capable of putting it out,” she said.

“I think it’s really elegant,” said Donna Farber, a professor of microbiology and immunology at Columbia University, describing the study. “They actually put some pieces together that hadn’t 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 it’s likely that [SARS-CoV-2] is particularly good at inducing it, but we don’t 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.

“They’re 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 it’s really hard to put out the fire.”

There’s another piece of the process, though, that suggests a way it might be stopped, and that’s 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 there’s 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…