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.