SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis | Wendisch, Dietrich, Mari, von Stillfried et al.

COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

由COVID-19诱发的急性呼吸窘迫综合征（acute respiratory distress syndrome, ARDS）常与持续性呼吸衰竭及高病死率相关，但其肺损伤的分子机制仍未完全阐明。本研究借助功能单细胞基因组学、免疫组织化学与电子显微镜技术，对两队列COVID-19相关ARDS患者的肺部免疫应答及肺脏病理特征进行了分析。研究发现，在COVID-19相关ARDS病程中，表达CD163的单核细胞衍生巨噬细胞发生蓄积，并获得了促纤维化转录表型。基因集富集分析与计算数据整合结果显示，COVID-19相关巨噬细胞与特发性肺纤维化中鉴定出的促纤维化巨噬细胞群体存在显著相似性。COVID-19相关ARDS与肺纤维化的临床、影像学、组织病理学及超微结构特征密切相关。将人类单核细胞暴露于SARS-CoV-2（而非甲型流感病毒或病毒RNA类似物）中，即可在体外诱导出相似的促纤维化表型。综上，本研究证实SARS-CoV-2可触发促纤维化巨噬细胞应答，并引发显著的纤维增生性ARDS。