IL-1b drives SARS-CoV-2 disease in vivo, independently of the inflammasome and pyroptotic signalling

Abstract Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Programmed cell death processes can drive inflammation, however, the relevance in the pathogenesis of severe COVID-19 is unclear. Pyroptosis is a pro-inflammatory form of regulated cell death initiated by inflammasomes and executed by the pore-forming protein gasdermin D (GSDMD). Using an established mouse-adapted SARS-CoV-2 virus and a combination of gene-targeted mice we found that deletion of the inflammasome (NLRP1/3 and the adaptor ASC) and pore forming proteins involved in pyroptosis (GSDMA/C/D/E) did not impact disease outcome or viral loads. Furthermore, we found that SARS-CoV-2 infection did not trigger GSDMD activation in mouse lungs. We did not observe any difference between WT animals and mice with compound deficiencies in upstream caspases C1/11/12−/−. This indicates that the classical canonical and non-canonical pro-inflammatory caspases known to process and activate IL-1β, IL-18 and GSDMD do not substantially contribute to SARS-CoV-2 pathogenesis. However, the loss of IL-1β, but not the absence of IL-18, ameliorated disease and enhanced survival in older animals compared to wildtype mice. Collectively, these findings indicate that IL-1β is an important factor contributing to severe SARS-CoV-2 disease, but its release was largely independent of inflammasome and pyroptotic pathways.