Comparative, single-cell analysis of COVID-19 and other respiratory diseases

项目总结 新冠肺炎病是由新型冠状病毒SARS-CoV-2引起的一种全球性的健康威胁疾病 传播、发病率和死亡率。据估计，至少25%的严重新冠肺炎幸存者 经历持续的呼吸道并发症。这强调了需要更好地了解细胞如何 SARS-CoV-2感染后，类型、再生谱系和细胞间通讯发生了变化 受影响组织中的调节机制和相互作用可能是Long-COVID的基础，这是长期的医学 新冠肺炎长途运输车的并发症。高通量单细胞RNA测序研究进展 (scRNA-seq)实现了对肺细胞普查的全面表征，这导致了 在动态平衡和疾病中的新细胞类型和细胞状态方面有大量的新发现。 然而，我们对细胞类型关系及其更高级的组织结构的理解仍然是 在新冠肺炎的背景下缺乏这种能力。我们实验室和人类细胞图谱(HCA)肺网络使用 来自健康个体的组织概要显示，鼻腔中有一组不同的上皮细胞 通道、呼吸道、肺泡和肠道共表达ACE2和TMPRSS2，与器官特异性疾病一致 新冠肺炎的介绍。最近，超过100万个细胞的scRNA-seq数据来自不止一个 数百名新冠肺炎患者公开可用，这提供了前所未有的解决方案和 统计学方法研究不同性别个体肺微环境的差异 新冠肺炎的介绍。这样的努力带来了几个计算挑战，因为高- 数据的维度以及scRNA-seq数据中蜂窝通信的分析工具和 与协调的多细胞基因表达计划的整合仍然是必要的。我们建议整合 高维scRNA-seq数据和实验室间批次效应校正，以便建立 统一标注的百余名新冠肺炎患者的单细胞图谱。这样的地图集将会 使我们能够描述细胞组成和细胞间相互作用的相似和不同之处 评估临床相关因素--如性别、年龄、药物和吸烟史--对组织的影响 组织。在我们大型综合对照队列中肺微环境的比较 新冠肺炎患者将发现常见的失调细胞类型和细胞间相互作用，这些细胞类型和细胞之间的相互作用可以 在治疗靶向的共同道路上。此外，对失调的细胞类型进行比较， 在其他肺部疾病中观察到的再生谱系和细胞间的相互作用将提供重要的 洞察如何重新调整现有药物的用途和对新冠肺炎长途运输者的推荐治疗 呼吸道并发症。

PROJECT SUMMARY COVID-19 disease, caused by the novel coronavirus SARS-CoV-2, is a global health threat due to its rapid spread, morbidity, and mortality. It is estimated that at least 25% of severe COVID-19 disease survivors experience persistent respiratory complications. This underscores the need to better understand how the cell types, regenerative lineages, and cell-cell communication are altered following SARS-CoV-2 infection and what regulatory mechanisms and interactions in affected tissue may underlie Long-COVID, the long-term medical complications in COVID-19 long-haulers. Recent advances in high-throughput single cell RNA-sequencing (scRNA-seq) have enabled comprehensive characterization of the cellular census of the lung, which has led to a remarkable number of novel findings in new cell types and cell states at homeostasis and in disease. However, our understanding of the cell type relationships and their higher order tissue organization is still lacking in the context of COVID-19. Analyses by our lab and the Human Cell Atlas (HCA) lung network using a compendium of tissues from healthy individuals revealed that a distinct subset of epithelial cells in the nasal passages, airways, alveoli, and gut co-express ACE2 and TMPRSS2, consistent with organ-specific disease presentations of COVID-19. More recently, over one million cells of scRNA-seq data from greater than one hundred COVID-19 patients became publicly available, which provides an unprecedented resolution and statistical power to study the variation in the lung cellular microenviroment between individuals with different presentation of COVID-19. Such an endeavor presents several computational challenges due to the high- dimensionality of the data and because analysis tools of cellular communication in scRNA-seq data and integration with coordinated multicellular gene expression programs are still needed. We propose to integrate high-dimensional scRNA-seq data and correct for batch effects between laboratories in order to build a uniformly annotated single-cell atlas of more than one hundred COVID-19 patients. Such an atlas would enable us to characterize the similarities and differences in cellular composition and cell-cell interactions and assess the effects of clinical correlates--such as gender, age, medications, and smoking history--on tissue organization. Comparisons between the lung microenvironment across our large, integrated cohort of control and COVID-19 patients will uncover commonly dysregulated cell types and cell-cell interactions that can inform on shared pathways to target therapeutically. Moreover, comparison of the dysregulated cell types, regenerative lineages, and cell-cell interactions to those observed in other lung diseases will provide important insight on how to repurpose existing drugs and recommended treatments for COVID-19 long haulers with respiratory complications.