Next generation sequencing transcriptome analysis of patient-derived macrophages stimulated with SARS-CoV-2 protein

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 re-programming 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. RNA profiles of patient-derived macrophages from SARS-CoV-2 convalescent patients and SARS-CoV-2 naïve individuals stimulated with SARS-CoV-2 spike protein, lipopolysaccharide or without stimulation.