An Indian-American scientist has discovered a potential strategy to prevent life-threatening inflammation, lung damage and organ failure in patients diagnosed with COVID-19. Published online in the journal Cell, the research coming from the lab of Dr Thirumala-Devi Kanneganti, an Indian-born researcher working at St. Jude Children's Research Hospital in 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 how the inflammatory cell death signaling 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, vice chair of the St Jude Department of Immunology.
Kanneganti was born and raised in Telangana. She received her undergraduate degree at Kakatiya University in Warangal, where she majored in Chemistry, Zoology, and Botany. She then received her M.Sc. and Ph.D from Osmania University in India. She joined St. Jude, in Memphis, Tennessee, USA, in 2007.
"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 said.
The other researchers were Shraddha Tuladhar, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R K 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 Health Science Center.
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 inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH), St Jude's said in a statement.
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.
The cellular and molecular mechanisms that comprehensively define cytokine storm was also lacking. 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, it said.
"The findings link inflammatory cell death induced by TNF-alpha and IFN-gamma to COVID-19,” Kanneganti said.
"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," she said.
"We were excited to connect these dots to understand how TNF-alpha and IFN-gamma trigger PANoptosis," said co-first author Rajendra Karki, a scientist in the Kanneganti laboratory.
"Indeed, understanding how PANoptosis contributes to disease and mortality is critical for identifying therapies," added co-first author Bhesh Raj Sharma, a scientist in the Kanneganti laboratory.
