Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19


  • S.J. Theobald
  • A. Simonis
  • T. Georgomanolis
  • C. Kreer
  • M. Zehner
  • H.S. Eisfeld
  • M.C. Albert
  • J. Chhen
  • S. Motameny
  • F. Erger
  • J. Fischer
  • J.J. Malin
  • J. Gräb
  • S. Winter
  • A. Pouikli
  • F. David
  • B. Böll
  • P. Koehler
  • K. Vanshylla
  • H. Gruell
  • I. Suárez
  • M. Hallek
  • G. Fätkenheuer
  • N. Jung
  • O.A. Cornely
  • C. Lehmann
  • P. Tessarz
  • J. Altmüller
  • P. Nürnberg
  • H. Kashkar
  • F. Klein
  • M. Koch
  • J. Rybniker


  • EMBO Molecular Medicine


  • EMBO Mol Med 13 (8): e14150


  • Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. Here we show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1β (IL-1β) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals. Furthermore, longitudinal analyses reveal robust S-protein-driven inflammasome activation in macrophages isolated from convalescent COVID-19 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID-19. Importantly, we show that S-protein-driven IL-1β secretion from patient-derived macrophages requires non-specific monocyte pre-activation in vivo to trigger NLRP3-inflammasome signaling. Our findings reveal that SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS-CoV-2 S-protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.