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.

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