Anti-inflammatory Drugs Demonstrate Efficacy Against COVID-19

With the hovering illness and death caused by the COVID-19 pandemic, the treatment options remain vague. Approaches to prevent life-threatening inflammation, lung damage and multi-organ failure in patients with COVID-19 have witnessed the discovery of a pathway that associates with hyperinflammatory immune responses. This led to the identification of potential therapies, that disrupt this process, as per research at St. Jude Children's Research Hospital, published online in the journal Cell. "Understanding the pathways and mechanism driving this inflammation is critical in developing effective treatment strategies," said corresponding author Thirumala-Devi Kanneganti, Ph.D., vice-chair of the St. Jude Department of Immunology.

The SARS-cov-2 virus infection is manifested by increased blood levels of multiple cytokines. These small signalling proteins are secreted primarily by immune cells to mediate inflammation and immunity in the body.

COVID-19, along with sepsis and inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH) , is said to be associated with cytokine storm – dramatically elevated cytokine levels in the blood. Hemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory syndrome of overactive immune system that damages the patient’s own tissues and organs, leading to death.

The molecular mechanisms that initiate the cytokine storm and cell death of innate immune cells in COVID-19 are not due to a single cytokine and the exact mechanism stays unclear.

Inflammatory Cellular Pathway:

The research team explored 28 cytokine combinations and observed that only one combination induced a form of inflammatory cell death – PANoptosis. The duo cytokines were tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma.

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PANoptosis is a type of cell death that coordinates three different cell death pathways – pyroptosis, apoptosis, and necroptosis, resulting in a cytokine storm. The proteins required for this include caspase-8 and STAT1. Deleting those proteins blocked PANoptosis in innate immune cells called macrophages.

The study found that the TNF-alpha and IFN-gamma combination triggered inflammatory tissue damage as similar to COVID-19 with rapid death. Antibodies against TNF-alpha and IFN-gamma associated inflammation demonstrated protection in mice from death associated with SARS-cov-2 infection, sepsis, HLH, and cytokine shock. This added insight for repurposing TNF-alpha and IFN-gamma blockers to treat COVID-19 and other fatal disorders associated with cytokine storm.

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"We have solved a major piece of the cytokine storm mystery by characterizing critical factors responsible for initiating this process, and thereby identifying a unique combination therapy using existing drugs that can be applied in the clinic to save lives", said Kanneganti.

Source-Medindia