Synergism of TNF-α, IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, Mortality in SARS-CoV-2
upstart writes in with an IRC submission for AzumaHazuki:
(From the abstract):
COVID-19 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, we found that only the combination of TNF- and IFN- induced inflammatory cell death characterized by pyroptosis, apoptosis, and necroptosis (PANoptosis). Mechanistically, TNF- and IFN- co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF- and IFN- 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. Furthermore, treating with neutralizing antibodies against TNF- and IFN- protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our 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.
TNF-: Tumor necrosis factor
IFN-: Interferon gamma
JAK: Janus kinase
STAT1: transcription 1
IRF1: Interferon regulatory factor 1
Article status is AIP (accepted, peer reviewed articles that are not yet assigned to volumes/issues, but are citable using DOI).
Full pre-print of the article is available for free from the abstract.
Journal Reference:
Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar1, et al. Synergism of TNF- and IFN- triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes, ScienceDirect, (DOI: 10.1016/j.cell.2020.11.025)
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