M Bader Stefanie, Scherer Lena, Schaefer Jan, Cooney James P, Mackiewicz Liana, Dayton Merle, Georgy Smitha Rose, Davidson Kathryn C, Allison Cody C, Herold Marco J, Strasser Andreas, Pellegrini Marc, Doerflinger Marcel
The Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC, 3052, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Cell Death Differ. 2025 Feb 28. doi: 10.1038/s41418-025-01459-x.
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.
过度炎症反应和细胞因子释放是重症 COVID-19 的标志。某些程序性细胞死亡过程可引发炎症，然而，它们在重症 COVID-19 发病机制中的作用尚不清楚。细胞焦亡是一种由炎性小体启动并由成孔蛋白 gasdermin D（GSDMD）执行的促炎性调节性细胞死亡形式。使用已建立的适应小鼠的 SARS-CoV-2 病毒和一组基因靶向小鼠，我们发现炎性小体（NLRP1/3 和接头蛋白 ASC）以及参与细胞焦亡的成孔蛋白（GSDMA/C/D/E）的缺失仅略微降低了 IL-1β 水平，并未影响疾病结局或病毒载量。此外，我们发现 SARS-CoV-2 感染并未触发小鼠肺部的 GSDMD 激活。最后，我们未观察到野生型动物与促炎性起始半胱天冬酶（C1/11/12）复合缺陷小鼠之间存在任何差异。这表明已知可加工和激活前 IL-1β、前 IL-18 和 GSDMD 的经典典型和非典型促炎性半胱天冬酶对 SARS-CoV-2 发病机制的贡献不大。然而，与野生型小鼠相比，IL-1β 的缺失而非 IL-18 的缺失改善了 SARS-CoV-2 感染动物的疾病状况并提高了存活率。总体而言，这些发现表明 IL-1β 是导致重症 SARS-CoV-2 疾病的重要因素，但其释放很大程度上独立于炎性小体和细胞焦亡途径。
