Single-Cell Omics Reveals Dyssynchrony of the Innate and Adaptive Immune System in Progressive COVID-19 [CITE-seq]

A dysregulated immune response against the SARS-CoV-2 virus plays a critical role in severe COVID-19. However, the molecular and cellular mechanisms by which the virus causes lethal immunopathology are poorly understood. Here, we utilize multi-omics single-cell analysis to probe dynamic immune responses in patients with stable or progressive manifestations of COVID-19, and assess the effects of tocilizumab, an anti-IL-6 receptor monoclonal antibody. Coordinated profiling of gene expression and cell lineage protein markers reveals a prominent type-1 interferon response across all immune cells, especially in progressive patients. An anti-inflammatory signature in monocytes and a pre-exhaustion phenotype in activated T cells are hallmarks of progressive disease. Single-cell T and B cell receptor repertoire analysis reveal a skewed clonal distribution of CD8 T cells and a primary B cell response with possible contribution from memory B cells. Our in-depth immune profiling reveals dyssynchrony of the innate and adaptive immune interaction in progressive COVID-19, which may contribute to delayed virus clearance and has implications for therapeutic intervention. 18 PBMC samples from 10 patients at various time points were studied. Age and sex matched healthy subjects (n=13) whose samples were collected before the COVID-19 pandemic were used as controls. Single-cell RNA sequencing (scRNA-seq) was performed, as well as surface protein libraries (CITE-seq), T cell receptor (TCR) libraries and B cell receptor (BCR) libraries. Detailed sample metadata are included in the tar archive with the processed data. The processed data for the control samples exist solely within the Seurat Rds file. There are no additional metadata or processed data files for the control samples, as there are for the COVID-19 samples.

针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的免疫应答失调，在重型新型冠状病毒肺炎（COVID-19）的发生发展中发挥关键作用。然而，该病毒引发致死性免疫病理损伤的分子与细胞机制仍知之甚少。本研究采用多组学单细胞分析技术，对表现为稳定或进展性新型冠状病毒肺炎表型的患者体内的动态免疫应答进行探究，并评估托珠单抗（tocilizumab）——一种抗白细胞介素6（IL-6）受体单克隆抗体——的治疗效果。通过联合分析基因表达与细胞谱系蛋白标志物的谱式特征，本研究发现，所有免疫细胞中均存在显著的I型干扰素应答，在进展型患者中尤为突出。单核细胞的抗炎特征与活化T细胞的预耗竭表型，是进展性疾病的标志性特征。单细胞T细胞受体（TCR）与B细胞受体（BCR）谱系分析显示，CD8阳性T细胞呈现克隆分布偏倚，且初始B细胞应答可能伴随记忆B细胞的参与。本研究通过深入的免疫细胞谱式分析，揭示了进展型新型冠状病毒肺炎患者体内先天免疫与适应性免疫交互作用的失同步现象，该现象可能导致病毒清除延迟，并为治疗干预提供了理论依据。本研究共纳入10例患者的18份外周血单个核细胞（PBMC）样本，采集自不同时间节点。以新冠疫情暴发前收集的、年龄与性别匹配的13例健康受试者作为对照。实验采用单细胞RNA测序（scRNA-seq）、表面蛋白文库测序（CITE-seq）、T细胞受体文库测序及B细胞受体文库测序技术。详细的样本元数据（metadata）已随处理后数据一同打包至tar归档文件中。对照组样本的处理数据仅存于Seurat Rds格式文件内，与新型冠状病毒肺炎样本不同，对照组样本无额外的元数据或处理后数据文件。