Journal Article

Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection

Strasser, Andreas, Doerflinger, Marcel, Mackiewicz, Liana, Wilcox, Stephen, Tanzer, Maria C., Batey, Daniel, Yip, Raymond K. H., Wang, Le, Pellegrini, Marc, V. L. Romero, David, Whitehead, Lachlan, Maluenda, Ana, Dayton, Merle, Phipson, Belinda, Jin, Xinyi, M. Bader, Stefanie, Pang, Jiyi, Gartner, Matthew J., Motyer, Allan J., Cooney, James P., Schaefer, Jan, Allison, Cody C., Samson, Andre L., Davidson, Kathryn C., Zaman, Ishrat, Bowden, Rory, Herold, Marco J., Rajasekhar, Pradeep, Brinkmann, Kerstin, Scherer, Lena, Sheerin, Dylan, Bhandari, Reet, Georgy, Smitha Rose, Chen, Siqi, Asselin-Labat, Marie-Liesse, Vince, James E., Schoffer, Kael

2025

Overview

Inflammation and excess cytokine release are hallmarks of severe COVID-19. While programmed cell death is known to drive inflammation, its role in SARS-CoV-2 pathogenesis remains unclear. Using gene-targeted murine COVID-19 models, we here find that caspase-8 is critical for cytokine release and inflammation. Loss of caspase-8 reduces disease severity and viral load in mice, and this occurs independently of its apoptotic function. Instead, reduction in SARS-CoV-2 pathology is linked to decreased IL-1β levels and inflammation. Loss of pyroptosis and necroptosis mediators in gene-targeted animals provides no additional benefits in mitigating disease outcomes beyond that conferred by loss of caspase-8. Spatial transcriptomic and proteomic analyses of caspase-8-deficient mice confirm that improved outcomes are due to reduced pro-inflammatory responses, rather than changes in cell death signalling. Elevated expression of caspase-8 and cFLIP in infected lungs, alongside caspase-8-mediated cleavage of N4BP1, a suppressor of NF-kB signalling, indicates a role of this signalling axis in pathological inflammation. Collectively, these findings highlight non-apoptotic functions of caspase-8 as a driver of severe COVID-19 through modulation of inflammation, not through the induction of apoptosis. During SARS-CoV-2 infection caspase-8 fuels harmful inflammation independent of apoptosis. Genetic loss of caspase-8 reduces cytokine levels, lowers viral load and mitigates disease severity, revealing non-apoptotic caspase-8 as a key driver of severe COVID-19.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/2 / 13/21 / 13/51 / 13/95 / 631/250/256/2516 / 631/326/596/4130 / 631/45/127/1220 / 64/60 / Animal models / Animals / Apoptosis / c-FLIP protein / CASP8 and FADD-Like Apoptosis Regulating Protein - genetics / CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism / Caspase 8 - genetics / Caspase 8 - metabolism / Caspase-8 / Cell death / Chemokines / COVID-19 / COVID-19 - genetics / COVID-19 - immunology / COVID-19 - pathology / COVID-19 - virology / Cytokines / Disease / Disease control / Disease Models, Animal / Fatalities / Female / Humanities and Social Sciences / Humans / Infections / Inflammation / Inflammation - immunology / Inflammation - pathology / Inflammation - virology / Interleukin-1beta - metabolism / Kinases / Lung - immunology / Lung - pathology / Lung - virology / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Mortality / multidisciplinary / Necroptosis / NF-κB protein / Pathogenesis / Pathology / Proteins / Proteomics / Pyroptosis / SARS-CoV-2 - immunology / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Signal Transduction / Spatial analysis / Transcriptomics / Tumor necrosis factor-TNF / Viral diseases / Viral Load