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

  • EMBO Mol Med. 2021 Aug 9;13(8):e14150. doi: 10.15252/emmm.202114150.
Sebastian J Theobald  1  2 ,  Alexander Simonis  1  2 ,  Theodoros Georgomanolis  3 ,  Christoph Kreer  4 ,  Matthias Zehner  4 ,  Hannah S Eisfeld  1  2 ,  Marie-Christine Albert  5  6 ,  Jason Chhen  1  2 ,  Susanne Motameny  3 ,  Florian Erger  3  7 ,  Julia Fischer  1  2  8 ,  Jakob J Malin  1  2 ,  Jessica Gräb  1  2 ,  Sandra Winter  1  2 ,  Andromachi Pouikli  9 ,  Friederike David  3 ,  Boris Böll  1 ,  Philipp Koehler  1  2  5 ,  Kanika Vanshylla  4 ,  Henning Gruell  4 ,  Isabelle Suárez  1  8 ,  Michael Hallek  1 ,  Gerd Fätkenheuer  1  8 ,  Norma Jung  1  8 ,  Oliver A Cornely  1  2  5  8 ,  Clara Lehmann  1  2  8 ,  Peter Tessarz  5  9 ,  Janine Altmüller  3 ,  Peter Nürnberg  2  3 ,  Hamid Kashkar  5  6 ,  Florian Klein  4  8 ,  Manuel Koch  10  11 ,  Jan Rybniker  1  2  8
Affiliations
  • 1. Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
  • 2. Faculty of Medicine and University Hospital of Cologne, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  • 3. Faculty of Medicine and University Hospital of Cologne, Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
  • 4. Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
  • 5. Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • 6. Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
  • 7. Faculty of Medicine, Institute of Human Genetics, University Hospital Cologne, Cologne, Germany.
  • 8. German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.
  • 9. Max Planck Research Group "Chromatin and Ageing", Max Planck Institute for Biology of Ageing, Cologne, Germany.
  • 10. Medical Faculty, Institute for Dental Research and Oral Musculoskeletal Biology, University of Cologne, Cologne, Germany.
  • 11. Medical Faculty, Center for Biochemistry, University of Cologne, Cologne, Germany.
PMID: 34133077 DOI: 10.15252/emmm.202114150
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.

Keywords
NLRP3; SARS-CoV-2; inflammasome; innate immunity; macrophage.