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

在COVID-19中负责病毒控制或过度炎症的先天免疫触发因素在很大程度上是未知的。我们已经生成了初步数据，显示SARS-CoV-2刺突蛋白（S蛋白）在来自COVID-19患者的巨噬细胞中引发NRLP 3-炎性体和释放白细胞介素-1 β（IL-1β），这是一种主要的促炎细胞因子，但在来自健康SARS-CoV-2初治个体的巨噬细胞中则没有。此外，我们已经观察到从恢复期COVID-19患者分离的巨噬细胞中S蛋白驱动的IL-1β分泌，这似乎与不同的基因表达特征相关，表明从COVID-19恢复后的先天免疫记忆。这些重要的发现需要对来自SARS-CoV-2初治个体和不同疾病阶段的COVID-19患者的单核细胞中的炎性小体激活进行深入和全面的分析。此外，纵向研究将炎性小体激活的发生和下降与临床结果相关联。我们将利用特异性SARS-CoV-2抗原、单核细胞炎性小体激活的明确标志物和纵向转录组学研究，对这一重要的促炎途径在COVID-19中的作用进行全面和多维的研究。我们的研究结果将揭示早期炎性小体激活是否与疾病结局相关，以及检测相应的标志物是否具有预测价值。通过关注主要的COVID-19疫苗抗原（S蛋白），我们将提供关于抗原驱动的先天免疫信号传导的重要见解，不仅在患病个体中，而且在接种疫苗的个体中。

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.