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A study in mice hints at drugs that could be helpful in treating severe coronavirus infections

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.

Researchers  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, they start seeing severe dramatic cell death.

This deadly duo doesn’t just kill cells. When  researchers injected the combination of TNF and interferon gamma, mice are dead like flies. Within 10 hours they just drop dead. 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 researchers 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.

Activating all three types of cell death together — an inflammation-producing process termed as PANoptosis by researchers— leads to an ever-escalating cytokine storm, “like a hurricane”.

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.

Drugs and antibodies that block the two immune chemicals exist and are used to treat some autoimmune diseases.

Source: R. Karki et al. COVID-19 cytokines and the hyperactive immune response: Synergism o.... October 29, 2020. doi: 10.1101/2020.10.29.361048

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