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

Bader, S M; Scherer, L; Bhandari, R; Motyer, AJ; Cooney, JP; Mackiewicz, L; Dayton, M; Sheerin, D; VLRomero D; Schaefer, J; Pang, J; Chen, S; Schoffer, K; Wang, L; Jin, X; Batey, D; Yip, RKH; Zaman, I; Rajasekhar, P; Gartner, MJ; Wilcox, S; Whitehead, L; Georgy, SR; Maluenda, A; Davidson, KC; Allison, CC; Bowden, R; Brinkmann, K; Asselin-Labat, ML; Phipson, B; Tanzer, MC; Herold, MJ; Samson, AL; Vince, JE; Strasser, A; Pellegrini, M; Doerflinger, M

Author(s): Bader, S M; Scherer, L; Bhandari, R; Motyer, AJ; Cooney, JP; Mackiewicz, L; Dayton, M; Sheerin, D; VLRomero D; Schaefer, J; Pang, J; Chen, S; Schoffer, K; Wang, L; Jin, X; Batey, D; Yip, RKH; Zaman, I; Rajasekhar, P; Gartner, MJ; Wilcox, S; Whitehead, L; Georgy, SR; Maluenda, A; Davidson, KC; Allison, CC; Bowden, R; Brinkmann, K; Asselin-Labat, ML; Phipson, B; Tanzer, MC; Herold, MJ; Samson, AL; Vince, JE; Strasser, A; Pellegrini, M; Doerflinger, M;
Details: Publication Year 2025-11-13,Volume 16,Issue #1,Page 9822
Journal Title: Nature Communications
Publication Type: Nov 13
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.
Publisher: Springer
Keywords: Animals; *Caspase 8/genetics/metabolism; *COVID-19/pathology/immunology/virology/genetics; Mice; *Inflammation/pathology/immunology/virology; *SARS-CoV-2/immunology; Mice, Knockout; Pyroptosis; CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism/genetics; Humans; Disease Models, Animal; Interleukin-1beta/metabolism; Lung/pathology/virology/immunology; Apoptosis; Mice, Inbred C57BL; Signal Transduction; Viral Load; Necroptosis; Male; Female
Research Division(s): Infection and Global Health; Blood Cells and Blood Cancer; Advanced Technology and Biology; Inflammation; Personalised Oncology
PubMed ID: 41233351
Publisher's Version: https://doi.org/10.1038/s41467-025-65098-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-65098-z.
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-12-05 09:23:47

Last Modified: 2025-12-05 09:29:35