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COVID-19 cytokines and the hyperactive immune response: Synergism of TNF-α and IFN-γ in triggering inflammation, tissue damage, and death.

  • Karki, Rajendra1
  • Sharma, Bhesh Raj1
  • Tuladhar, Shraddha1
  • Williams, Evan Peter2
  • Zalduondo, Lillian2
  • Samir, Parimal1
  • Zheng, Min1
  • Sundaram, Balamurugan1
  • Banoth, Balaji1
  • Malireddi, R K Subbarao1
  • Schreiner, Patrick3
  • Neale, Geoffrey4
  • Vogel, Peter5
  • Webby, Richard6
  • Jonsson, Colleen Beth2
  • Kanneganti, Thirumala-Devi1
  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 2 Department of Microbiology, Immunology, & Biochemistry, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
  • 3 The Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 4 Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 5 Animal Resources Center and Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 6 Department of Infectious Disease, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Published Article
bioRxiv : the preprint server for biology
Publication Date
Oct 29, 2020
DOI: 10.1101/2020.10.29.361048
PMID: 33140051


The COVID-19 pandemic has caused significant morbidity and mortality. Currently, there is a critical shortage of proven treatment options and an urgent need to understand the pathogenesis of multi-organ failure and lung damage. Cytokine storm is associated with severe inflammation and organ damage during COVID-19. However, a detailed molecular pathway defining this cytokine storm is lacking, and gaining mechanistic understanding of how SARS-CoV-2 elicits a hyperactive inflammatory response is critical to develop effective therapeutics. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combined production of TNF-α and IFN-γ specifically induced inflammatory cell death, PANoptosis, characterized by gasdermin-mediated pyroptosis, caspase-8-mediated apoptosis, and MLKL-mediated necroptosis. Deletion of pyroptosis, apoptosis, or necroptosis mediators individually was not sufficient to protect against cell death. However, cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of PANoptosis protected mice from TNF-α and IFN-γ-induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. In vivo neutralization of both TNF-α and IFN-γ in multiple disease models associated with cytokine storm showed that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models, demonstrating the broad physiological relevance of this mechanism. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. The findings also provide a molecular and mechanistic description for the term cytokine storm. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancers where TNF-α and IFN-γ synergism play key pathological roles.

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