The scientists led by Thirumala-Devi Kanneganti, vice chair of Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee, identified the drugs after discovering that the hyperinflammatory immune response associated with Covid-19 leads to tissue damage and multi-organ failure in mice by triggering inflammatory cell death pathways.
The researchers detailed in a paper published in the journal “Cell” how the inflammatory cell death signalling pathway worked, which led to potential therapies to disrupt the process.
“Understanding the pathways and mechanism driving this inflammation is critical to develop effective treatment strategies,” said Kanneganti who was born in Telangana and earned her undergraduate degree at Kakatiya University in Warangal.
“This research provides that understanding. We also identified the specific cytokines that activate inflammatory cell death pathways and have considerable potential for treatment of Covid-19 and other highly fatal diseases, including sepsis,” she informed.
She worked with Bhesh Raj Sharma, Rajendra Karki and others at her lab for the research that helps increase understanding of the pathways and mechanism that drives Covid-19 inflammation so researchers can develop effective treatment strategies.
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.
Kanneganti’s 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.
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.