Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of >895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell–cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.

支持严重急性呼吸系统综合症冠状病毒 2 感染中免疫反应功能失调的机制尚不清楚。我们分析了来自 73 名 2019 年冠状病毒病 (COVID-19) 患者和 75 名日本血统健康对照者的超过 895,000 个外周血单核细胞的单细胞转录组和 T 细胞和 B 细胞受体 (BCR)，以及宿主遗传数据。COVID-19 患者表现出低比例的非经典单核细胞 (ncMono)。我们报告了 COVID-19 中从经典单核细胞到 ncMono 的细胞转变下调，CXCL10减少ncMono 在严重疾病中的表达。细胞间通讯分析推断在严重 COVID-19 中涉及 ncMono 的细胞相互作用减少。BCR 的克隆扩增在患者的浆母细胞中很明显。COVID-19 全基因组关联研究确定的推定疾病基因显示单核细胞和树突细胞中的细胞类型特异性表达。IFNAR2基因座 (rs13050728)的 COVID-19 相关风险变异具有上下文特异性和单核细胞特异性表达数量性状基因座效应。我们的研究强调了先天免疫细胞在 COVID-19 严重程度中的生物学和宿主遗传参与。