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

Nat Commun. 2025 Nov 13;16(1):9822. doi: 10.1038/s41467-025-65098-z.

Stefanie M Bader ¹ ², Lena Scherer ³ ⁴, Reet Bhandari ³ ⁴, Allan J Motyer ³ ⁴, James P Cooney ³ ⁴, Liana Mackiewicz ³, Merle Dayton ³, Dylan Sheerin ³ ⁴, David V L Romero ³ ⁴, Jan Schaefer ³ ⁴, Jiyi Pang ³ ⁴, Siqi Chen ³ ⁵, Kael Schoffer ³, Le Wang ³ ⁴, Xinyi Jin ³ ⁴, Daniel Batey ³, Raymond K H Yip ³ ⁴, Ishrat Zaman ³, Pradeep Rajasekhar ³ ⁴, Matthew J Gartner ⁶, Stephen Wilcox ³ ⁴, Lachlan Whitehead ³ ⁴, Smitha Rose Georgy ⁷, Ana Maluenda ³, Kathryn C Davidson ³ ⁴, Cody C Allison ³, Rory Bowden ³ ⁴, Kerstin Brinkmann ³ ⁴, Marie-Liesse Asselin-Labat ³ ⁴, Belinda Phipson ³ ⁴, Maria C Tanzer ³ ⁴, Marco J Herold ³ ⁴ ⁸ ⁹, Andre L Samson ³ ⁴, James E Vince ³ ⁴, Andreas Strasser ³ ⁴, Marc Pellegrini ¹⁰ ¹¹ ¹², Marcel Doerflinger ¹³ ¹⁴

Affiliations

1 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, VIC, Australia. [email protected].
2 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. [email protected].
3 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, VIC, Australia.
4 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
5 College of Life Sciences, Nankai University, Tianjin, China.
6 Department of Microbiology and Immunology, the University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
7 Section of Anatomic Pathology, Melbourne Veterinary School, Faculty of Science, University of Melbourne, Werribee, Victoria, VIC, Australia.
8 Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, VIC, Australia.
9 School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, VIC, Australia.
10 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, VIC, Australia. [email protected].
11 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. [email protected].
12 Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia. [email protected].
13 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, VIC, Australia. [email protected].
14 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. [email protected].

PMID: 41233351 DOI: 10.1038/s41467-025-65098-z

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.

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