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Caspase-8’s non-apoptotic role is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection.

ABSTRACT: Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Programmed cell death is known to drive inflammation, however, its relevance in the pathogenesis of severe COVID-19 is unclear. Using a combination of gene-targeted murine models and transcriptomic approaches we found that excessive cytokine release and inflammation are dependent on caspase-8. Loss of caspase-8 significantly reduced disease severity and viral loads in vivo. Importantly, this phenotype was not attributable to caspase-8’s role in apoptosis but was instead linked to a decrease in IL-1β levels and inflammation. Combined deficiency of pyroptosis, necroptosis, and apoptosis mediators (Caspase1/11/12/8/Ripk3-/-) provided no added benefit in ameliorating disease outcomes compared to C8/R3-/- mice. Transcriptional profiling of lung tissues in mice lacking caspase-8, and in compound mutants lacking caspase-8 and other additional caspases and mediators, confirmed that disease outcomes were not associated with transcription differences in cell death pathways, but rather to differences in pro-inflammatory responses. The expression of caspase-8 and FLIP was increased in the lungs of SARS-CoV-2 infected mice. Collectively, these findings identify a pivotal role for caspase-8 in driving the pathogenesis of severe SARS-CoV-2 infection through the modulation of pro-inflammatory cytokines but not through the induction of apoptosis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

DISEASE(S): Covid-19

SUBMITTER: Maria Tanzer

LAB HEAD: Marcel Doerflinger

PROVIDER: PXD057656 | Pride | 2025-09-20

REPOSITORIES: Pride

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Project description:COVID-19 has rapidly circulated around the globe and caused significant morbidity and mortality. The disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage and patient mortality. Although initial cytokine cascades may be beneficial to the host for clearing the virus, enhanced production of pro-inflammatory cytokines and increasing levels in the systemic circulation, referred to as cytokine storm, can promote tissue damage by inducing inflammatory cell death in both infected and bystander cells. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combination of TNF-α and IFN-γ specifically induced cell death characterized by GSDME¬–mediated pyroptosis, caspase-8–mediated apoptosis, and MLKL–mediated necroptosis. Cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. However, deletion of pyroptosis, apoptosis, or necroptosis individually was not sufficient to protect against 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 inflammatory cell death protected mice from TNF-α and IFN-γ–induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. To determine the physiological relevance of protection, we neutralized both TNF-α and IFN-γ in multiple disease models associated with cytokine storm and found that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models. 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. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancer where TNF-α and IFN-γ synergism play key pathological roles.

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Caspase-8’s non-apoptotic role is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection.

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