The researchers knew that these so-called cytokine storms were harmful, but they didn’t know why the SARS-CoV-2 virus seemed so good at triggering them.
The study revealed 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, to find and destroy pathogens. They do this by eating, or actually surrounding and absorbing, threats like viruses to prevent them from infecting other cells.
Once a bad actor is absorbed, these cells have what can best be described as a cellular garbage collector, called an endosome, which normally shuts down the infectious agent.
However, in the case of the SARS-CoV-2 virus, that does not happen. The virus breaks out of the endosome and escapes into the cell body, where it begins to make copies of itself.
“Viruses don’t just get absorbed, but once they get absorbed, the virus starts to replicate, 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 it happens to these protective cells, it sets off a next-level set of alarm bells.
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 “burning death”.
Pyroptosis is a recently recognized phenomenon. It occurs in other diseases as well, such as sepsis.
“When cells die from pyroptosis, they release all sorts of inflammatory proteins that cause fever and call more immune cells to the site,” Lieberman said. It triggers a cascade of crisis signals that is very difficult to stop.
“We have no way of dealing with that once it starts. It’s like a small fire. It spreads and explodes and no fire extinguisher is capable of putting it out,” he 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 together some pieces that hadn’t been put together before.” She was not involved in the investigation.
By comparing blood cells from healthy people with those from people who came to the hospital with COVID-19 and blood from people who had pneumonia from other causes, the researchers found that this process appears to occur more often with COVID-19.
“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’s 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, such as obesity or diabetes, are at higher risk for serious outcomes with Covid-19. Those conditions are already associated with some level of inflammation in the body.
“They are much, much more likely to start these inflammatory fires,” he said. “They kind of have a slow, slow burn anyway. And once it starts, it’s really hard to put the fire out.”
The role of antibodies
However, there is another part of the process that suggests a way it could be stopped, and that is how the virus enters these white blood cells.
Monocytes and macrophages lack ACE-2 receptors, the gates the virus uses to attach to and infect other cell types. Instead, the virus enters these cells. due to another immune system helper: Y-shaped antibodies that attach to the virus in an attempt to prevent it from attaching to our cells.
When antibodies catch viruses, the tail of the antibody, called the FC portion, sticks out. That stalk acts like a flag to draw monocytes and macrophages down to let them know there’s a bad guy to catch.
Not all monocytes recognize the same antibodies. The study found that people with COVID-19 tended to have more than one unusual type of monocyte that had CD16 receptors. These receptors recognize the antibody stems that the body produces to fight the SARS-CoV-2 virus.
Those antibodies connect to monocytes with CD16 receptors, causing the cell to take up the virus. Once inside, the virus starts trying to copy itself, triggering the damaging inflammatory reaction.
John Wherry, director of the Institute of Immunology at the Perelman School of Medicine at the University of Pennsylvania, said that’s something we’ve been wondering about with Covid-19 infections, if there might be some sort of increased disease antibody . Wherry was not involved in the study.
He said this can also happen with other infections, such as dengue fever. The more times a person is infected with the dengue virus, the sicker they become with each subsequent attack. That is the opposite of what is supposed to happen. A person who recovers from an infection is usually better protected against future infections.
Wherry said there is no evidence that the antibodies that facilitate these severe inflammatory reactions come from previous infections or from other types of coronavirus. He said that antibodies are produced rapidly in infections and that the ones at work here were probably produced in response to the person’s current illness. In that way, it is different from what happens with dengue.
However, antibodies generated by vaccines do not appear to facilitate monocyte infections and the inflammatory cascades that follow. They tested it in the studio.
“I think what’s interesting about this is that it could provide a clue and maybe even some drug targets for why some of the inflammation that we see in severe COVID patients might start in the wrong way or get out of control,” Wherry said. “So that’s where I think this is quite interesting.”