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<p>Inflammation and excess cytokine release are hallmarks of severe COVID-19. While programmed cell death is known to drive inflammation, its role in SARS-CoV-2 pathogenesis remains unclear. Using gene-targeted murine COVID-19 models, we here find that caspase-8 is critical for cytokine release and inflammation. Loss of caspase-8 reduces disease severity and viral load in mice, and this occurs independently of its apoptotic function. Instead, reduction in SARS-CoV-2 pathology is linked to decreased IL-1β levels and inflammation. Loss of pyroptosis and necroptosis mediators in gene-targeted animals provides no additional benefits in mitigating disease outcomes beyond that conferred by loss of caspase-8. Spatial transcriptomic and proteomic analyses of caspase-8-deficient mice confirm that improved outcomes are due to reduced pro-inflammatory responses, rather than changes in cell death signalling. Elevated expression of caspase-8 and cFLIP in infected lungs, alongside caspase-8-mediated cleavage of N4BP1, a suppressor of NF-kB signalling, indicates a role of this signalling axis in pathological inflammation. Collectively, these findings highlight non-apoptotic functions of caspase-8 as a driver of severe COVID-19 through modulation of inflammation, not through the induction of apoptosis.</p>

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Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月13日

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  • Stefanie M. Bader,
  • Lena Scherer,
  • Reet Bhandari,
  • Allan J. Motyer,
  • James P. Cooney,
  • Liana Mackiewicz,
  • Merle Dayton,
  • Dylan Sheerin,
  • David V. L. Romero,
  • Jan Schaefer,
  • Jiyi Pang,
  • Siqi Chen,
  • Kael Schoffer,
  • Le Wang,
  • Xinyi Jin,
  • Daniel Batey,
  • Raymond K. H. Yip,
  • Ishrat Zaman,
  • Pradeep Rajasekhar,
  • Matthew J. Gartner,
  • Stephen Wilcox,
  • Lachlan Whitehead,
  • Smitha Rose Georgy,
  • Ana Maluenda,
  • Kathryn C. Davidson,
  • Cody C. Allison,
  • Rory Bowden,
  • Kerstin Brinkmann,
  • Marie-Liesse Asselin-Labat,
  • Belinda Phipson,
  • Maria C. Tanzer,
  • Marco J. Herold,
  • Andre L. Samson,
  • James E. Vince,
  • Andreas Strasser,
  • Marc Pellegrini,
  • Marcel Doerflinger

摘要

Inflammation and excess cytokine release are hallmarks of severe COVID-19. While programmed cell death is known to drive inflammation, its role in SARS-CoV-2 pathogenesis remains unclear. Using gene-targeted murine COVID-19 models, we here find that caspase-8 is critical for cytokine release and inflammation. Loss of caspase-8 reduces disease severity and viral load in mice, and this occurs independently of its apoptotic function. Instead, reduction in SARS-CoV-2 pathology is linked to decreased IL-1β levels and inflammation. Loss of pyroptosis and necroptosis mediators in gene-targeted animals provides no additional benefits in mitigating disease outcomes beyond that conferred by loss of caspase-8. Spatial transcriptomic and proteomic analyses of caspase-8-deficient mice confirm that improved outcomes are due to reduced pro-inflammatory responses, rather than changes in cell death signalling. Elevated expression of caspase-8 and cFLIP in infected lungs, alongside caspase-8-mediated cleavage of N4BP1, a suppressor of NF-kB signalling, indicates a role of this signalling axis in pathological inflammation. Collectively, these findings highlight non-apoptotic functions of caspase-8 as a driver of severe COVID-19 through modulation of inflammation, not through the induction of apoptosis.