Cell's paper details the mechanisms of inflammatory cell death, tissue damage, and death in SARS-CoV-2 infection and cytokine shock syndrome, TNF-α and IFN-γ

november 23, 2020 // the ---COVID-19 pandemic continues to cause major illnesses and deaths, while treatment options remain limited.
a new study, researchers from St. Jude Children's Research Hospital in the United States have discovered a potential strategy to prevent life-threatening inflammation, lung damage and organ failure in PATIENTs with COVID-19.
published online November 18, 2020 in the journal Cell, the paper is titled "Synergism of TNF-α and IFN-γ Triggersingsing cells, tissue damage, and mortality in SARS-CoV-2 infect and cytokine shock syndromes."
from Cell, 2020, doi:10.1016/j.cell.2020.11.025.
the authors identified drug candidates after finding that the excessive inflammatory immune response associated with COVID-19 led to tissue damage and multi-organ failure in mice by triggering the death of inflammatory cells.
they detail how the inflammatory cell death signaling path path is working, helping to develop potential treatments to disrupt the process.
"Understanding the paths and mechanisms that drive this inflammation is critical to developing effective treatment strategies," said Dr. Thirumala-Devi Kanneganti, co-author of the paper and deputy director of the Department of Immunology at St. Jude Children's Research Hospital.
study provides this understanding.
we have also identified specific cytokines that activate the pathways of inflammatory cell death and have considerable potential for the treatment of COVID-19 and other highly fatal diseases, including sepsis.
"COVID-19, cytokines and inflammatory cell death COVID-19 are caused by SARS-CoV-2 coronavirus.
less than a year, the virus has killed more than 1.2 million people and sickened millions more.
virus infection is characterized by elevated levels of multiple cytokines in the blood.
these small molecular proteins are secreted mainly by immune cells to ensure rapid response that limits the virus.
cytokines can also cause inflammation. the phrase
cytokine storms is used to describe sharp increases in cytokine levels in the blood and other immune changes that can also be observed in inflammatory diseases such as COVID-19, sepsis, and haemophilic lymphatic tissue cell disease (HLH).
in COVID-19 and other diseases, the exact pathways for initiating cytokine storms and subsequent inflammation, lung damage, and organ failure are unclear.
also lack the cellular and molecular mechanisms to fully identify cytokine storms.
Kanneganti's team focused on a select group of the highest elevated cytokines in PATIENT-19 patients.
found that no cytokine induces congenital immune cell death.
the authors then experimented with 28 cytokine combinations and found that a combination of only two cytokines induced an inflammatory cell death form previously described by Kaneganti, PANoptosis.
these two cytokines are tumor necrotum α (TNF-α) and interferon γ (IFN-γ).
PANoptosis is a unique type of cell death characterized by the coordination of three different pathways to cell death--- pyroposis, apoptosis, and necroptosis.
, PANoptosis triggers inflammation through cell death, leading to the release of more cytokines and inflammatory molecules.
the authors found that blocking the path of individual cell death was ineffective in preventing cell death caused by TNF-α and IFN-γ.
looked closely at the proteins that make up these pathways, they found that several proteins, including caspase-8 and STAT1, were necessary for PANoptosis to respond to these cytokines.
these proteins can block PANoptosis in innococular cells called macrophages.
's potential to re-use TNF-α and IFN-γ blockers to treat COVID-19 is due to the fact that TNF-α and IFN-γ are produced during COVID-19 and cause the death of inflammatory cells, the authors question whether these cytokines are the cause of clinical manifestations and fatal effects of the disease.
they found that the combination of TNF-α and IFN-γ triggered tissue damage and inflammation, similar to the symptoms of COVID-19, and was associated with rapid death.
currently clinically, neutral antibodies α TNF-γ and IFN-γ are used to treat inflammatory diseases.
the authors found that treating mice with these antibodies protected them from SARS-CoV-2 infections, sepsis, HLH, and cytokine shock-related deaths.
"These results link TNF-α and IFN-γ-induced inflammatory cell death to COVID-19," said Kanneganti, a research scientist.
results also suggest that the treatment for this combination of cytokines may be a candidate not only for COVID-19 but also for several other deadly diseases associated with cytokine storms. Dr Rajendra Karki, co-author of the
paper and a researcher at Kanneganti Labs, added, "We are pleased to be able to connect these points to understand how TNF-α and IFN-γ trigger PANoptosis."
fact, understanding how PANoptosis causes disease and death is critical to determining treatment.
" redefinition of cytokine storms based on this basic study, Kanneganti and her colleagues proposed a definition of cytokine storms, placing cytokines at the center of the process through the death of inflammatory cells mediated by PANoptosis.
authors note that PANoptosis leads to the release of more cytokines and inflammatory molecules, which in turn exacerbates systemic inflammation.
Kanneganti said, "By identifying the key factors responsible for initiating this process, we have solved an important link in the mystery of cytokine storms, thereby identifying a unique combination therapy using existing drugs."
these drugs have been used clinically to save lives.
" (Bioon.com) Reference: 1. Rajendra Karki et al. Synergism of TNF-α and IFN-γ triggersingsingaly cell death, damage tissue, and mortality in SARS-CoV-2 infect and cytokine shock syndromes. Cell, 2020, doi:10.1016/j.cell.2020.11.025.2.Scientists identify possible COVID-19 treatment