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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

Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar, Evan Peter Williams, Lillian Zalduondo, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R. K. Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel, Richard Webby, Colleen Beth Jonsson, Thirumala-Devi Kanneganti
doi: https://doi.org/10.1101/2020.10.29.361048
Rajendra Karki
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Bhesh Raj Sharma
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Shraddha Tuladhar
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Evan Peter Williams
2Department of Microbiology, Immunology, & Biochemistry, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
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Lillian Zalduondo
2Department of Microbiology, Immunology, & Biochemistry, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
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Parimal Samir
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Min Zheng
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Balamurugan Sundaram
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Balaji Banoth
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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R. K. Subbarao Malireddi
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Patrick Schreiner
3The Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Geoffrey Neale
4Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Peter Vogel
5Animal Resources Center and Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Richard Webby
6Department of Infectious Disease, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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Colleen Beth Jonsson
2Department of Microbiology, Immunology, & Biochemistry, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
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Thirumala-Devi Kanneganti
1Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
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  • For correspondence: Thirumala-Devi.Kanneganti@StJude.org
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SUMMARY

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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted October 29, 2020.
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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
Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar, Evan Peter Williams, Lillian Zalduondo, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R. K. Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel, Richard Webby, Colleen Beth Jonsson, Thirumala-Devi Kanneganti
bioRxiv 2020.10.29.361048; doi: https://doi.org/10.1101/2020.10.29.361048
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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
Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar, Evan Peter Williams, Lillian Zalduondo, Parimal Samir, Min Zheng, Balamurugan Sundaram, Balaji Banoth, R. K. Subbarao Malireddi, Patrick Schreiner, Geoffrey Neale, Peter Vogel, Richard Webby, Colleen Beth Jonsson, Thirumala-Devi Kanneganti
bioRxiv 2020.10.29.361048; doi: https://doi.org/10.1101/2020.10.29.361048

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