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Published online in the journal Cell, research from the laboratory of Dr. Thirumala-Devi Kanneganti, an Indian-born researcher at St. Jude Children’s Research Hospital in Tennessee, identified the drugs after discovering that the immune response Hyperinflammatory disease associated with COVID-19 leads to tissue damage and multi-organ failure in mice by triggering inflammatory cell death pathways.
The researchers detailed how the inflammatory cell death signaling pathway worked, leading to possible therapies to disrupt the process.
“Understanding the pathways and mechanisms that cause this inflammation is critical to developing effective treatment strategies,” said Kanneganti, vice president of the Department of Immunology at St Jude.
Kanneganti was born and raised in Telangana. He received his BA from Kakatiya University in Warangal, where he specialized in Chemistry, Zoology, and Botany. He then received his M.Sc. and Ph.D. from the University of Osmania in India. He joined St. Jude, in Memphis, Tennessee, USA, in 2007.
“This research provides that understanding. We also identify specific cytokines that activate inflammatory cell death pathways and have considerable potential for the treatment of COVID-19 and other highly deadly diseases, including sepsis,” he said.
The other researchers were Shraddha Tuladhar, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, RK Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel and Richard Webby of St. Jude; and Evan Peter Williams, Lillian Zalduondo, and Colleen Beth Jonsson of the University of Tennessee Center for Health Sciences.
COVID-19 is caused by the SARS-CoV-2 virus. The infection has killed more than 1.2 million people in less than a year and sickened millions more.
The infection is characterized by increased blood levels of multiple cytokines. These small proteins are mainly secreted 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 levels of cytokines in the blood and other immune changes that have also been seen in COVID-19, sepsis, and inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH), St Jude’s said in a release.
But the specific pathways that initiate the cytokine storm and subsequent inflammation, lung damage, and organ failure in COVID-19 and the other disorders were unclear.
The cellular and molecular mechanisms that comprehensively define the cytokine storm were also lacking. Kanneganti’s team focused on a select set of the highest cytokines in COVID-19 patients. The scientists showed that no single cytokine induced cell death in innate immune cells, he said.
“The findings link TNF-alpha and IFN-gamma-induced inflammatory cell death to COVID-19,” Kanneganti said.
“The results also suggest that therapies that target this combination of cytokines are candidates for rapid clinical trials for the treatment of not only COVID-19, but several other often fatal disorders associated with the cytokine storm,” he said.
“We were excited to connect these dots to understand how TNF-alpha and IFN-gamma trigger PANoptosis,” said co-lead author Rajendra Karki, a scientist at the Kanneganti lab.
“Indeed, understanding how PANoptosis contributes to disease and mortality is critical to identifying therapies,” added co-author Bhesh Raj Sharma, a scientist in Kanneganti’s lab.
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