How two immune system chemicals may trigger COVID-19’s deadly cytokine storms

Exactly how the coronavirus kills is a mystery. But part of the problem may be a partnership between just two immune system chemicals that triggers deadly organ damage.

In mice, a combination of immune chemicals called TNF alpha and gamma interferon trips a domino chain of biochemical reactions that ultimately leads to three types of cell death, researchers report October 29 at That wave of cell death further feeds an escalation of immune chemicals, known as a cytokine storm, that leads to more cell death and causes tissue and organ damage and failure.

If the same process happens in people with severe COVID-19, the research points to several existing drugs that might help calm the cytokine storm and prevent severe disease or aid recovery. The preliminary results, however, have not yet been reviewed by other scientists.

Study after study has found that people with severe COVID-19 have elevated levels of inflammation-stimulating chemicals called cytokines in their blood compared with healthy people, says immunologist Thirumala-Devi Kanneganti of St. Jude Children’s Research Hospital in Memphis, Tenn. But the mechanism by which cytokines can lead to organ failure and death isn’t known.

Kanneganti and colleagues selected eight of the most commonly elevated cytokines in severely ill COVID-19 patients to see how the cytokines affect cells growing in lab dishes. Alone, none of cytokines caused harm to infection-fighting macrophage cells. But when the researchers treated macrophages with a cocktail of all eight cytokines, “we were seeing dramatic cell death, unbelievable, through the roof,” Kanneganti says. The team then tried various combinations of cytokines and discovered that only the pairing of TNF alpha and gamma interferon was deadly to macrophages.

That’s surprising, says Mohamed Lamkanfi, an immunologist at Ghent University in Belgium who was not involved in the study. Those cytokines have been studied for decades and weren’t previously implicated in killing cells.

This deadly duo doesn’t just kill cells. “When we injected the combination of TNF and interferon gamma, mice are dead like flies. Within 10 hours they just drop dead,” Kanneganti says. And those mice had symptoms similar to those seen in people with severe COVID-19, such as low numbers of infection-fighting T cells and signs of liver and tissue damage.

Next, Kanneganti and her colleagues deciphered how the two cytokines kill cells and mice. In a series of experiments, the researchers found that the combo triggers three kinds of cell death: apoptosis, pyroptosis and necroptosis.

Apoptosis is a quiet kind of programmed cell death that happens often, even in healthy people. It’s necessary for proper development and health, including avoiding cancer. Cells infected with a virus will often set off this self-destruct mechanism. Their deaths and removal from the body may help shield other cells from becoming infected.

Pyroptosis and necroptosis are messier, causing cells to spill their guts and release cytokines and debris that can trigger more inflammation. Researchers knew that these gorier deaths are involved in some inflammatory conditions, but apoptosis wasn’t previously known to rile up the immune system, Kanneganti says.

Activating all three types of cell death together — an inflammation-producing process Kanneganti calls PANoptosis — leads to an ever-escalating cytokine storm, “like a hurricane,” she says.

Researchers have thought that those three varieties of cell death were triggered by different biochemical switches. But Kanneganti’s group found that all three types of death can result from a single chain reaction, or pathway. At the trailhead of the biochemical pathway sit proteins known as STAT1 and JAK. Inappropriate chemical actions by both have been implicated in some types of cancer, and inhibitors of these proteins are being tested in cancer therapies.

One inhibitor of JAK, a drug called baricitinib, is already being tested against the coronavirus (SN: 5/13/20). Preliminary evidence suggests that when given to hospitalized patients along with the antiviral drug remdesivir, baricitinib can shorten hospital stays even more than remdesivir alone has been shown to do.   

The researchers also found that blocking TNF alpha and gamma interferon protected mice infected with SARS-CoV-2 — the virus that causes COVID-19 — from dying. Mice with other inflammatory conditions were also protected from dying when both cytokines were blocked, and to a lesser extent when only one was blocked. Those findings suggest that both cytokines must be blocked to have an effect, Lamkanfi says.

Drugs and antibodies that block the two immune chemicals exist and are used to treat some autoimmune diseases. For instance, TNF alpha inhibitors are used to treat Crohn’s disease, ulcerative colitis, and rheumatoid and psoriatic arthritis.

Kanneganti’s data are convincing that the two cytokines may be involved in what’s going wrong in severely ill COVID-19 patients, says Craig Coopersmith, a sepsis researcher and director of the Emory Critical Care Center in Atlanta. “It’s mechanistically fascinating and gives multiple potential [drug] targets that are worth exploring,” he says.

But he’s skeptical that blocking the two cytokines will be as effective in people as it was in mice. “I have cured mouse sepsis 15 times, and I know my colleagues have cured mouse COVID,” he says. But “most of the time when you do the trials in people, they turn out to be negative.”

And just because a drug could plausibly work doesn’t mean it will, of course. For instance, an antibody drug called tocilizumab, which blocks another cytokine called IL-6, did not show a benefit for treating COVID-19 in recent clinical trials (SN: 10/23/20).

In people, the triad of cell death triggered by TNF alpha and gamma interferon isn’t necessarily the only thing killing COVID-19 patients, Coopersmith emphasizes. Blood clotting and cardiovascular issues and lung damage from mechanical ventilation are also big problems. Nevertheless, the new “mechanistically phenomenal study” gives researchers a good place to start teasing out what goes wrong in people with severe COVID-19, he says, and learning how to fix it.

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