tetano
Editor, Senior Moderator
Nat Commun
. 2025 Nov 13;16(1):9822.
doi: 10.1038/s41467-025-65098-z. Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection
Stefanie M Bader[SUP] 1 2 [/SUP], Lena Scherer[SUP] 3 4 [/SUP], Reet Bhandari[SUP] 3 4 [/SUP], Allan J Motyer[SUP] 3 4 [/SUP], James P Cooney[SUP] 3 4 [/SUP], Liana Mackiewicz[SUP] 3 [/SUP], Merle Dayton[SUP] 3 [/SUP], Dylan Sheerin[SUP] 3 4 [/SUP], David V L Romero[SUP] 3 4 [/SUP], Jan Schaefer[SUP] 3 4 [/SUP], Jiyi Pang[SUP] 3 4 [/SUP], Siqi Chen[SUP] 3 5 [/SUP], Kael Schoffer[SUP] 3 [/SUP], Le Wang[SUP] 3 4 [/SUP], Xinyi Jin[SUP] 3 4 [/SUP], Daniel Batey[SUP] 3 [/SUP], Raymond K H Yip[SUP] 3 4 [/SUP], Ishrat Zaman[SUP] 3 [/SUP], Pradeep Rajasekhar[SUP] 3 4 [/SUP], Matthew J Gartner[SUP] 6 [/SUP], Stephen Wilcox[SUP] 3 4 [/SUP], Lachlan Whitehead[SUP] 3 4 [/SUP], Smitha Rose Georgy[SUP] 7 [/SUP], Ana Maluenda[SUP] 3 [/SUP], Kathryn C Davidson[SUP] 3 4 [/SUP], Cody C Allison[SUP] 3 [/SUP], Rory Bowden[SUP] 3 4 [/SUP], Kerstin Brinkmann[SUP] 3 4 [/SUP], Marie-Liesse Asselin-Labat[SUP] 3 4 [/SUP], Belinda Phipson[SUP] 3 4 [/SUP], Maria C Tanzer[SUP] 3 4 [/SUP], Marco J Herold[SUP] 3 4 8 9 [/SUP], Andre L Samson[SUP] 3 4 [/SUP], James E Vince[SUP] 3 4 [/SUP], Andreas Strasser[SUP] 3 4 [/SUP], Marc Pellegrini[SUP] 10 11 12 [/SUP], Marcel Doerflinger[SUP] 13 14 [/SUP]
Affiliations
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.
. 2025 Nov 13;16(1):9822.
doi: 10.1038/s41467-025-65098-z. Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection
Stefanie M Bader[SUP] 1 2 [/SUP], Lena Scherer[SUP] 3 4 [/SUP], Reet Bhandari[SUP] 3 4 [/SUP], Allan J Motyer[SUP] 3 4 [/SUP], James P Cooney[SUP] 3 4 [/SUP], Liana Mackiewicz[SUP] 3 [/SUP], Merle Dayton[SUP] 3 [/SUP], Dylan Sheerin[SUP] 3 4 [/SUP], David V L Romero[SUP] 3 4 [/SUP], Jan Schaefer[SUP] 3 4 [/SUP], Jiyi Pang[SUP] 3 4 [/SUP], Siqi Chen[SUP] 3 5 [/SUP], Kael Schoffer[SUP] 3 [/SUP], Le Wang[SUP] 3 4 [/SUP], Xinyi Jin[SUP] 3 4 [/SUP], Daniel Batey[SUP] 3 [/SUP], Raymond K H Yip[SUP] 3 4 [/SUP], Ishrat Zaman[SUP] 3 [/SUP], Pradeep Rajasekhar[SUP] 3 4 [/SUP], Matthew J Gartner[SUP] 6 [/SUP], Stephen Wilcox[SUP] 3 4 [/SUP], Lachlan Whitehead[SUP] 3 4 [/SUP], Smitha Rose Georgy[SUP] 7 [/SUP], Ana Maluenda[SUP] 3 [/SUP], Kathryn C Davidson[SUP] 3 4 [/SUP], Cody C Allison[SUP] 3 [/SUP], Rory Bowden[SUP] 3 4 [/SUP], Kerstin Brinkmann[SUP] 3 4 [/SUP], Marie-Liesse Asselin-Labat[SUP] 3 4 [/SUP], Belinda Phipson[SUP] 3 4 [/SUP], Maria C Tanzer[SUP] 3 4 [/SUP], Marco J Herold[SUP] 3 4 8 9 [/SUP], Andre L Samson[SUP] 3 4 [/SUP], James E Vince[SUP] 3 4 [/SUP], Andreas Strasser[SUP] 3 4 [/SUP], Marc Pellegrini[SUP] 10 11 12 [/SUP], Marcel Doerflinger[SUP] 13 14 [/SUP]
Affiliations
- PMID: 41233351
- DOI: 10.1038/s41467-025-65098-z
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.