シングルセル情報とゲノム情報の統合解析によるCOVID-19重症化メカニズムの解明

• Published in: 日本薬理学会年会要旨集 p. 1-B-S05-2
• Main Authors: 奥崎, 大介, 山口, 勇太, Liu, Yu-Chen, 村上, 輝明, 榊原, 修平, 友藤, 嘉彦, 福永, 興壱, 熊ノ郷, 淳, 南宮, 湖, 竹島, 雄介, 森田, 貴義, 岡田, 随象, 白井, 雄也, Wing, James B, 曽根原, 究人, 田中, 拓, 枝廣, 龍哉, 平田, 陽彦, 元岡, 大祐, 加藤, 保宏, 李, 昊, 武田, 吉人
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2023
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.97.0_1-B-S05-2

Mechanisms underpinning the dysfunctional immune response in SARS-CoV-2 infection are not yet fully understood. In addition, the functional roles of the genetic variants identified by COVID-19 genome-wide association study (GWAS) remain elusive, especially in non-European ancestry. We analyzed single-cell transcriptomes and T and B cell receptors of > 895,000 peripheral blood mononuclear cells from 73 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, suggesting that the dysfunction of ncMono might be closely involved in the immunopathology of COVID-19 severity.  Clonal expansions of B cell receptors were evident in plasmablasts of patients. Putative disease genes identified by the GWAS of severe phenotypes showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had COVID-19-specific and monocyte-specific expression quantitative trait loci effects, indicating the enrichment of host genetic risk in innate immune cells. Our multimodal and integrative single-cell analyses highlight biological and host genetic involvement of innate immune cells in COVID-19 severity.