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

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.

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Publication Details

Journal
Nature Communications
Published
2025-11-13
DOI
https://doi.org/10.1038/s41467-025-65098-z
Citations
1
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
0.81

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

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

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

Abstract

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.

Nature CommunicationsVol. 16(1)
University of Technology Sydney (AU), The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), La Trobe University (AU), Nankai University (CN), Centenary Institute (AU), Peter Doherty Institute (AU), Hôpital Pellegrin (FR), Olivia Newton-John Cancer Wellness & Research Centre (AU), Victoria University (AU)
U.S. Department of Health and Human Services, Medical Advances Without Animals Trust, State Government of Victoria, Medical Research Council, National Health and Medical Research Council
Openalex Percentile: Top 22%
Inflammasome and immune disorders
0.81
DOIOpen Access PDFOpenAlex
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