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

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

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65098-z

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