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