RT Journal Article
SR Electronic
T1 COVID-19 cytokines and the hyperactive immune response: Synergism of TNF-α and IFN-γ in triggering inflammation, tissue damage, and death
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.29.361048
DO 10.1101/2020.10.29.361048
A1 Rajendra Karki
A1 Bhesh Raj Sharma
A1 Shraddha Tuladhar
A1 Evan Peter Williams
A1 Lillian Zalduondo
A1 Parimal Samir
A1 Min Zheng
A1 Balamurugan Sundaram
A1 Balaji Banoth
A1 R. K. Subbarao Malireddi
A1 Patrick Schreiner
A1 Geoffrey Neale
A1 Peter Vogel
A1 Richard Webby
A1 Colleen Beth Jonsson
A1 Thirumala-Devi Kanneganti
YR 2020
UL http://biorxiv.org/content/early/2020/10/29/2020.10.29.361048.abstract
AB 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 StatementThe authors have declared no competing interest.