Implicating Gene and Cell Networks Responsible for Differential COVID-19 Host Responses via an Interactive Single Cell Web Portal

Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a datamine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to probe these via a new interactive web portal (http://toppcell.cchmc.org/). As examples, we develop three hypotheses: (1) a multicellular signaling cascade among alternatively differentiated monocyte-derived macrophages whose tasks include T cell recruitment and activation; (2) novel platelet subtypes with drastically modulated expression of genes responsible for adhesion, coagulation and thrombosis; and (3) a multilineage cell activator network able to drive extrafollicular B maturation via an ensemble of genes strongly associated with risk for developing post-viral autoimmunity.

已有多项研究获取了宿主针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的应答单细胞转录组图谱。然而目前极为缺失的是一款可支持用户比对、探索细胞图谱，从而获取研究见解并提出全新假说的数据挖掘资源平台。为解决这一问题，本研究整合了新型冠状病毒肺炎（COVID-19）及其他对照条件下的血液、支气管肺泡灌洗液（bronchoalveolar lavage）及组织样本相关数据集，并针对每种细胞类型、亚型、临床状态及组织分区构建了基因特征模块汇编。本研究通过一款全新的交互式网络门户（http://toppcell.cchmc.org/）展示了探索该资源的具体方法。作为示例，本研究提出了三项假说：（1）经交替分化的单核细胞源性巨噬细胞之间存在一条多细胞信号级联反应，其功能涵盖T细胞的募集与活化；（2）存在新型血小板亚型，其黏附、凝血及血栓形成相关基因的表达水平发生显著改变；（3）存在一条多谱系细胞激活网络，可通过一组与病毒感染后自身免疫病发病风险显著相关的基因，驱动滤泡外B细胞成熟。