Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19.
Sebastian J Theobald, Alexander Simonis, Theodoros Georgomanolis, Christoph Kreer, Matthias Zehner, Hannah S Eisfeld, Marie-Christine Albert, Jason Chhen, Susanne Motameny, Florian Erger, Julia Fischer, Jakob J Malin, Jessica Gräb, Sandra Winter, Andromachi Pouikli, Friederike David, Boris Böll, Philipp Koehler, Kanika Vanshylla, Henning Gruell, Isabelle Suárez, Michael Hallek, Gerd Fätkenheuer, Norma Jung, Oliver A Cornely, Clara Lehmann, Peter Tessarz, Janine Altmüller, Peter Nürnberg, Hamid Kashkar, Florian Klein, Manuel Koch, Jan Rybniker
Author Information
Sebastian J Theobald: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Alexander Simonis: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany. ORCID
Theodoros Georgomanolis: Faculty of Medicine and University Hospital of Cologne, Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany. ORCID
Christoph Kreer: Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany. ORCID
Matthias Zehner: Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Hannah S Eisfeld: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Marie-Christine Albert: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Jason Chhen: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Susanne Motameny: Faculty of Medicine and University Hospital of Cologne, Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany. ORCID
Florian Erger: Faculty of Medicine and University Hospital of Cologne, Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Julia Fischer: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany. ORCID
Jakob J Malin: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany. ORCID
Jessica Gräb: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Sandra Winter: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Andromachi Pouikli: Max Planck Research Group "Chromatin and Ageing", Max Planck Institute for Biology of Ageing, Cologne, Germany.
Friederike David: Faculty of Medicine and University Hospital of Cologne, Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany. ORCID
Boris Böll: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Philipp Koehler: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Kanika Vanshylla: Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Henning Gruell: Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany. ORCID
Isabelle Suárez: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Michael Hallek: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Gerd Fätkenheuer: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Norma Jung: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Oliver A Cornely: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Clara Lehmann: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Peter Tessarz: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. ORCID
Janine Altmüller: Faculty of Medicine and University Hospital of Cologne, Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Peter Nürnberg: Faculty of Medicine and University Hospital of Cologne, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Hamid Kashkar: Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Florian Klein: Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
Manuel Koch: Medical Faculty, Institute for Dental Research and Oral Musculoskeletal Biology, University of Cologne, Cologne, Germany.
Jan Rybniker: Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany. ORCID
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.
