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Theobald, S.J., Simonis, A., Georgomanolis, T., Kreer, C., Zehner, M., Eisfeld, H.S., Albert, M.C., Chhen, J., Motameny, S. [...] Cornely, O.A., Lehmann, C., Tessarz, P., Altmüller, J., Nürnberg, P., Kashkar, H., Klein, F., Koch, M., and Rybniker, J.

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


nnate 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.

Read more at EMBO Molecluar Medicine e14150