IL-1β drives SARS-CoV-2-induced disease independently of the inflammasome and pyroptosis signalling
- Author(s)
- MBader S; Scherer, L; Schaefer, J; Cooney, JP; Mackiewicz, L; Dayton, M; Georgy, SR; Davidson, KC; Allison, CC; Herold, MJ; Strasser, A; Pellegrini, M; Doerflinger, M;
- Journal Title
- Cell Death & Differentiation
- Publication Type
- Feb 28
- Abstract
- Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Certain programmed cell death processes can drive inflammation, however, their role 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 panel 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) only marginally reduced IL-1β levels and did not impact disease outcome or viral loads. Furthermore, we found that SARS-CoV-2 infection did not trigger GSDMD activation in mouse lungs. Finally, we did not observe any difference between WT animals and mice with compound deficiencies in the pro-inflammatory initiator caspases (C1/11/12(-/-)). This indicates that the classical canonical and non-canonical pro-inflammatory caspases known to process and activate pro-IL-1β, pro-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 SARS-CoV-2 infected animals compared to wildtype mice. Collectively, these findings demonstrate 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.
- Publisher
- Springer Nature
- Research Division(s)
- Infection and Global Health; Blood Cells and Blood Cancer
- PubMed ID
- 40016339
- Publisher's Version
- https://doi.org/10.1038/s41418-025-01459-x
- Open Access at Publisher's Site
https://doi.org/10.1038/s41418-025-01459-x- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-04-10 09:58:41
Last Modified: 2025-04-10 10:00:14