IL-1beta drives SARS-CoV-2-induced disease independently of the inflammasome and pyroptosis signalling

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

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;
Details: Publication Year 2025-07,Volume 32,Issue #7,Page 1353-1366
Journal Title: Cell Death & Differentiation
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-1beta 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-1beta, pro-IL-18 and GSDMD do not substantially contribute to SARS-CoV-2 pathogenesis. However, the loss of IL-1beta, 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-1beta 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
Keywords: Animals; *Pyroptosis; *Interleukin-1beta/metabolism/genetics; *Inflammasomes/metabolism; *COVID-19/pathology/virology/metabolism/immunology; *SARS-CoV-2; Mice; Signal Transduction; Phosphate-Binding Proteins/metabolism; Mice, Inbred C57BL; Mice, Knockout; Intracellular Signaling Peptides and Proteins/metabolism; Humans; Lung/virology/pathology/metabolism; Gasdermins
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: 2025-07-28 03:12:06