Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection
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.
Article Details
Authors (37)
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
Marcel Doerflinger