The St. Jude investigators then tried 28 cytokine combinations and found just one duo that, working together, induced a form of inflammatory cell death previously described by Kanneganti as PANoptosis.
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 investigators 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.
Neutralising antibodies against TNF-alpha and IFN-gamma are currently used to treat inflammatory diseases in the clinic.
"The findings link inflammatory cell death induced by TNF-alpha and IFN-gamma to Covid-19," said Kanneganti who received her M.Sc. and Ph.D. from Osmania University in India.
"The results also suggest that therapies that target this cytokine combination are candidates for rapid clinical trials for treatment of not only Covid-19, but several other often fatal disorders associated with cytokine storm."
Co-first author Karki added: "We were excited to connect these dots to understand how TNF-alpha and IFN-gamma trigger PANoptosis."
"Indeed, understanding how PANoptosis contributes to disease and mortality is critical for identifying therapies," Sharma said.link