Scientists discover a potential strategy to prevent inflammation in COVID-19 patients

Reviewed by Emily Henderson, B.Sc.November 19, 2020

The COVID-19 pandemic continues to cause significant illness and death while treatment options remain limited. Scientists at St. Jude Children’s Research Hospital have discovered a potential strategy to prevent life-threatening inflammation, lung damage, and organ failure in patients with COVID-19. The research appeared online in the journal Cell.

Scientists 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 the functioning of the inflammatory cell death signaling pathway, which led to potential therapies to disrupt the process.

“Understanding the pathways and mechanisms that drive this inflammation is critical to developing effective treatment strategies,” said corresponding author Thirumala-Devi Kanneganti, Ph.D., vice president of the St. Jude Department of Immunology. “This research provides this insight. We have also identified specific cytokines that activate inflammatory cell death pathways and have significant potential for the treatment of COVID-19 and other highly fatal diseases, including sepsis.”

COVID-19, cytokines and inflammatory cell death

COVID-19 is caused by the SARS-CoV-2 virus. The infection killed more than 1.2 million people in less than a year and made millions more sick.

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 limit the virus. Some cytokines also trigger inflammation.

The phrase cytokine storm has been used to describe dramatically elevated cytokine levels in the blood and other immune changes that have also been seen in COVID-19, sepsis, and inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH).

But the specific pathways that initiate the cytokine storm and subsequent inflammation, lung damage, and organ failure in COVID-19 and other disorders were unclear. The cellular and molecular mechanisms that fully define the cytokine storm were also missing.

Kanneganti’s team focused on a select set of the highest cytokines in COVID-19 patients. Scientists showed that no single cytokine induced cell death in innate immune cells.

The St. Jude researchers then tried 28 combinations of cytokines and found only one pair that, working together, induced a form of inflammatory cell death previously described by Kanneganti as PANoptosis. Cytokines are tumor necrosis factor (TNF) -alpha and interferon (IFN) -gamma.

PANoptosis is a unique type of cell death that features the coordination of three different cell death pathways: pyroptosis, apoptosis and necroptosis. PANoptosis fuels inflammation through cell death, resulting in the release of more cytokines and inflammatory molecules.

Researchers demonstrated that blocking of single cell death pathways was ineffective in arresting cell death caused by TNF-alpha and IFN-gamma. A closer look at the proteins that make up the pathways identified several, including caspase-8 and STAT1, which were essential for PANoptosis in response to these cytokines. Eliminating those proteins blocked PANoptosis in innate immune cells called macrophages.

Potential for repurposing TNF-alpha and IFN-gamma blockers for the treatment of COVID-19

Because TNF-alpha and IFN-gamma are produced during COVID-19 and cause inflammatory cell death, researchers wondered 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 mirroring the symptoms of COVID-19 along with rapid death.

Neutralizing antibodies against TNF-alpha and IFN-gamma are currently used to treat inflammatory diseases in the clinic. The researchers found that treatment with these antibodies protected the mice from death associated with SARS-CoV-2 infection, sepsis, HLH, and cytokine shock.

The findings link TNF-alpha and IFN-gamma-induced inflammatory cell death to COVID-19, “Kanneganti said.” The findings also suggest that therapies that target this cytokine combination are candidates for rapid clinical trials for the treatment of more than just COVID-19. , but many other often fatal disorders associated with the cytokine storm. “

Thirumala-Devi Kanneganti, PhD, Corresponding Author of the Study, Vice President of the St. Jude Department of Immunology

Co-first author Rajendra Karki, Ph.D., a scientist from the Kanneganti lab added, “We were thrilled to connect these dots to understand how TNF-alpha and IFN-gamma trigger PANoptosis.” First author, Bhesh Raj Sharma, Ph.D., a scientist with the Kanneganti lab, added: “Indeed, understanding how PANoptosis contributes to disease and mortality is critical to identifying therapies.”

Redefine the cytokine storm

Based on this fundamental research, Kanneganti and his colleagues proposed a definition of a cytokine storm that places cytokine-mediated inflammatory cell death via PANoptosis at the center of the process. Researchers noted that PANoptosis causes the release of more cytokines and inflammatory molecules, which intensifies systemic inflammation.

“We solved an important piece of the cytokine storm mystery by characterizing the critical factors responsible for initiating this process, and then by identifying a unique combination therapy that uses existing drugs that can be applied in the clinic to save lives,” he said. Kanneganti.