Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19. Issue 8 (16th June 2021)

• Record Type: Journal Article
• Authors: Theobald, Sebastian J; Simonis, Alexander; Georgomanolis, Theodoros; Kreer, Christoph; Zehner, Matthias; Eisfeld, Hannah S; Albert, Marie‐Christine; Chhen, Jason; Motameny, Susanne; Erger, Florian; Fischer, Julia; Malin, Jakob J; Gräb, Jessica; Winter, Sandra; Pouikli, Andromachi; David, Friederike; Böll, Boris; Koehler, Philipp; Vanshylla, Kanika; Gruell, Henning; Suárez, Isabelle; Hallek, Michael; Fätkenheuer, Gerd; Jung, Norma; Cornely, Oliver A; Lehmann, Clara; Tessarz, Peter; Altmüller, Janine; Nürnberg, Peter; Kashkar, Hamid; Klein, Florian; Koch, Manuel; Rybniker, Jan;
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 8(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-06-16
• Subjects: inflammasome -- innate immunity -- macrophage -- NLRP3 -- SARS‐CoV‐2; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202114150
• Languages: English
• ISSNs: 1757-4676

Abstract

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. SYNOPSIS: SARS‐CoV‐2 infection leads to hyperinflammatory syndromes in a subset of patients. We show that human primary macrophages require genome‐wide transcriptional modifications for pro‐inflammatory signaling upon stimulation with the SARS‐CoV‐2 surface glycoprotein (S‐protein). The SARS‐CoV‐2 spike protein drives NRLP3 inflammasome activation in COVID‐19 patient derived macrophages. Macrophages from SARS‐CoV‐2 naïve individuals fail to process and subsequently secrete IL‐1β upon stimulation with the S‐protein. The S‐protein is a pathogen‐associated molecular pattern (PAMP) requiring macrophage pre‐activation for NLRP3 inflammasome formation. Inflammasome activation and IL‐1β signaling represent attractive targets for pharmacological interventions in severe COVID‐19. Abstract : SARS‐CoV‐2 infection leads to hyperinflammatory syndromes in a subset of patients. We show that human primary macrophages require genome‐wide transcriptional modifications for pro‐inflammatory signaling upon stimulation with the SARS‐CoV‐2 surface glycoprotein (S‐protein).