Deciphering SARS-CoV-2 mediated inflammasome activation in COVID-19 patient-derived myeloid cells

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Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. We have generated preliminary data showing that the SARS-CoV-2 spike protein (S-protein) primes the NRLP3-inflammasome and release of interleukin-1β (IL-1β), a major pro-inflammatory cytokine, in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals. In addition, we have observed S-protein driven IL-1β secretion in macrophages isolated from convalescent COVID-19 patients which seems to correlate with a distinct gene expression signature suggesting innate immune memory after recovery from COVID-19. These important findings require in depth and comprehensive analyses of inflammasome activation in monocytes derived from SARS-CoV-2 naïve individuals and COVID-19 patients in different stages of disease. Furthermore, longitudinal studies will correlate onset and decline of inflammasome activation to clinical outcome. We will exploit specific SARS-CoV-2 antigens, well defined markers of monocyte inflammasome activation and longitudinal transcriptomic studies to generate a global and multi-dimensional picture on the role of this important pro-inflammatory pathway in COVID-19. Our findings will reveal, whether early inflammasome activation correlates with disease outcome and whether detection of respective markers is of predictive value. By focusing on the major COVID-19 vaccine antigen (S-protein), we will provide important insights on antigen driven innate immune signaling not only in diseased individuals but also in vaccinated individuals.