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

Inflammation and cytokine release are hallmarks of severe COVID-19. While pro-grammed cell death is known to drive inflammation, its role in SARS-CoV-2 patho-genesis remains unclear. Using gene-targeted murine COVID-19 models with tran-scriptomic and proteomic analyses, we found that caspase-8 is critical for cytokine release and inflammation. Loss of caspase-8 reduced disease severity and viral loads in mice, and interestingly, this occurred independently of its apoptotic func-tion. Instead, reduction in SARS-CoV-2 pathology was linked to decreased IL-1β levels and inflammation. Loss of pyroptosis and necroptosis mediators, in gene-targeted animals, provided no additional benefits in mitigating disease outcomes beyond that conferred by loss of caspase-8. Transcriptional profiling of caspase-8 knockout animals confirmed that improved outcomes were due to reduced pro-inflammatory responses, rather than changes in cell death signaling. Elevated ex-pression of caspase-8 and FLIP in infected lungs, alongside caspase-8 mediated cleavage of the NF-kB signaling suppressor N4BP1, suggests a role of this signal-ing axis in overt inflammation. Collectively, these findings highlight non-apoptotic caspase-8 as a driver of severe COVID-19 through modulation of inflammation, not through the induction of apoptosis.