Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19
Authors
- 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
Journal
- EMBO Molecular Medicine
Citation
- EMBO Mol Med 13 (8): e14150
Abstract
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.