COVID-19 Breakthrough! PANoptosis Discovered To Be Main Cause For Inflammation In COVID-19. TNF-alpha And IFN-gamma Blockers Can Help Treat COVID-19

COVID-19 Breakthroughs: A new breakthrough study led by researchers from St. Jude Children's Research Hospital-Memphis along with scientist from University of Tennessee Health Science Center have discovered that inflammation in COVID-19 patients were not just caused by cytokine storms per se or even just by bradykinin storms but rather were triggered by what is known as PANoptosis.


 
PANoptosis is a unique type of cell death that features 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.
 
The COVID-19 disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, the study team found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by pyroptosis, apoptosis, and necroptosis (Collectively known as PANoptosis).
 
Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase8/FADD–mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death.
 
In addition, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock.
 
The study findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.
 
The study findings were published in the peer reviewed journal: Cell. https://www.cell.com/cell/pdf/S0092-8674(20)31542-7.pdf
 
The ongoing COVID-19 pandemic continues to cause significant illness and death while treatment options remain limited.
 
The study team from St. Jude Children's Research Hospital has discovered a potential strategy to prevent life-threatening inflammation, lung damage, and organ failure in patients with COVID-19.
 
The team also identified the potential 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 study team detailed how the inflammatory cell death signaling pathway worked, which led to potential therapies to disrupt the process.
 
Corresponding author Dr Thirumala-Devi Kanneganti, Ph.D., vice chair of the St. Jude Department of Immunology told Thailand Medical News, "Understanding the pathways and mechanism driving this inflammation is critical to develop effective treatment strategies. 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."
 
The COVID-19 disease is caused by the SARS-CoV-2 virus. The infection has killed more than 1.36 million people in less than one year and sickened millions more.
 
The viral 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.
 
Wrongly, 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).
 
However the specific pathways that initiate the cytokine storm and the subsequent inflammation, lung damage and organ failure in COVID-19 and the other disorders was unclear till now. The cellular and molecular mechanisms that comprehensively define cytokine storm were also lacking.
 
Dr 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.

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The study team 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 cytokines are tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma.
 
The study team showed that blocking individual cell death pathways was ineffective in stopping cell death caused by TNF-alpha and IFN-gamma. A closer look at proteins that make up the pathways identified several, including caspase-8 and STAT1, that were essential for PANoptosis in response to these cytokines. Deleting those proteins blocked PANoptosis in innate immune cells called macrophages.
 
As a result of TNF-alpha and IFN-gamma being produced during COVID-19 and causes inflammatory cell death, the study team questioned whether these cytokines were responsible for the clinical manifestations and deadly effects of the disease.
 
The team 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.
 
Currently neutralizing antibodies against TNF-alpha and IFN-gamma are used to treat inflammatory diseases in the clinic. The study team found that treatment with these antibodies protected mice from death associated with SARS-CoV-2 infection, sepsis, HLH and cytokine shock.
 
Dr Kanneganti stressed, “The study findings link inflammatory cell death induced by TNF-alpha and IFN-gamma to COVID-19. 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."

Dr Rajendra Karki, Ph.D., a scientist in the Kanneganti laboratory and co-first author of the study added, "We were excited to connect these dots to understand how TNF-alpha and IFN-gamma trigger PANoptosis."
 
Co-first author Dr Bhesh Raj Sharma, Ph.D., a scientist in the Kanneganti laboratory, further added, "Indeed, understanding how PANoptosis contributes to disease and mortality is critical for identifying therapies."
 
These breakthrough research findings by Dr Kanneganti and her colleagues have proposed a new definition of a cytokine storm that puts the cytokine-mediated inflammatory cell death via PANoptosis at the center of the process. The researchers noted that PANoptosis results in the release of more cytokines and inflammatory molecules, which intensifies systemic inflammation.
 
Dr Kanneganti added, "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."
 
The study team suggests that Emapalumab, an anti-IFN-γ antibody that was recently approved by the US FDA to treat refractory, recurrent, or progressive HLH and the study data suggest that the therapeutic potential of combining this with an anti–TNF-α antibody could be beneficial to treat COVID-19. https://pubmed.ncbi.nlm.nih.gov/32374962/

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