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Here we show that the SARS\u2010CoV\u20102 spike protein (S\u2010protein) primes inflammasome formation and release of mature interleukin\u20101\u03b2 (IL\u20101\u03b2) in macrophages derived from COVID\u201019 patients but not in macrophages from healthy SARS\u2010CoV\u20102 na\u00efve individuals. Furthermore, longitudinal analyses reveal robust S\u2010protein\u2010driven inflammasome activation in macrophages isolated from convalescent COVID\u201019 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID\u201019. Importantly, we show that S\u2010protein\u2010driven IL\u20101\u03b2 secretion from patient\u2010derived macrophages requires non\u2010specific monocyte pre\u2010activation\n                    <jats:italic>in vivo<\/jats:italic>\n                    to trigger NLRP3\u2010inflammasome signaling. Our findings reveal that SARS\u2010CoV\u20102 infection causes profound and long\u2010lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS\u2010CoV\u20102 S\u2010protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202114150","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T06:35:06Z","timestamp":1623825306000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":146,"title":["Long\u2010lived macrophage reprogramming drives spike protein\u2010mediated inflammasome activation in COVID\u201019"],"prefix":"10.1038","volume":"13","author":[{"given":"Sebastian 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