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Publications

Journal Article Ppublish

PubMed: 40016339 DOI: 10.1038/s41418-025-01459-x

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

Cell Death Differ 32(7):1353-1366

Authors: Stefanie M Bader, Lena Scherer, Jan Schaefer, James P Cooney, Liana Mackiewicz, Merle Dayton, Smitha Rose Georgy, Kathryn C Davidson, Cody C Allison, Marco J Herold, Andreas Strasser, Marc Pellegrini, Marcel Doerflinger

Affiliations

  • The Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC, 3052, Australia.
  • Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Anatomic Pathology-Veterinary Biosciences, Melbourne Veterinary School, University of Melbourne, Werribee, VIC, 3030, Australia.
  • Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.
  • School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia.
  • The Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC, 3052, Australia.
  • Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
  • The Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC, 3052, Australia.
  • Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.

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.

MeSH

Cells, Genes, Cell Differentiation, Sars-Cov-2, Inflammasomes, Caspases, Covid-19, Pyroptosis, Severe Acute Respiratory Syndrome-Related Coronavirus, Cell Death