The COVID-19 pandemic continues to cause significant illness and death while treatment options remain limited.
In a new study, researchers have discovered a potential strategy to prevent life-threatening inflammation, lung damage, and organ failure in patients with COVID-19.
They identified the drugs after discovering that the hyper-inflammatory immune response linked to COVID-19 leads to tissue damage and multi-organ failure by triggering inflammatory cell death pathways.
The research was conducted by St. Jude Children’s Research Hospital scientists.
COVID-19 is caused by the SARS-CoV-2 virus. The infection has killed more than 1.2 million people in less than one year and sickened millions more.
The infection is marked by increased blood levels of multiple cytokines. These small proteins are secreted primarily by immune cells to ensure a rapid response to restrict the virus. Some cytokines also trigger inflammation.
The phrase cytokine storm has been used to describe the dramatically elevated cytokine levels in the blood and other immune changes that have also been observed in COVID-19, sepsis, and other inflammatory disorders.
But the specific pathways that initiate the cytokine storm and the subsequent inflammation, lung damage, and organ failure in COVID-19 and the other disorders were unclear.
In the study, the team focused on a select set of the most elevated cytokines in COVID-19 patients. The scientists showed that no single cytokine-induced cell death in innate immune cells.
They then tried 28 cytokine combinations and found just one duo that, working together, induced a form of inflammatory cell death.
The cytokines are tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma.
The investigators showed that blocking individual cell death pathways was ineffective in stopping cell death caused by TNF-alpha and IFN-gamma.
Because TNF-alpha and IFN-gamma are produced during COVID-19 and cause inflammatory cell death, the team questioned whether these cytokines were responsible for the clinical manifestations and deadly effects of the disease.
They found that the TNF-alpha and IFN-gamma combination triggered tissue damage and inflammation that mirror the symptoms of COVID-19 along with rapid death.
Neutralizing antibodies against TNF-alpha and IFN-gamma are currently used to treat inflammatory diseases in the clinic.
The team found that treatment with these antibodies protected mice from death linked to SARS-CoV-2 infection, sepsis, and cytokine shock.
The results suggest that therapies that target this cytokine combination are candidates for rapid clinical trials for the treatment of not only COVID-19 but several other often fatal disorders associated with cytokine storm.
One author of the study is Thirumala-Devi Kanneganti, Ph.D., vice-chair of the St. Jude Department of Immunology.
The study is published in Cell.
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