Decoding the cellular mechanisms of COVID-19 severe disease susceptibility in patients with chronic respiratory disease

项目总结 新型冠状病毒(SARS-CoV-2)及相关疾病(新冠肺炎)是世界性的全球性威胁 由于它的高度传染性和迅速传播，它对经济和公共卫生造成了巨大的影响。开发最优产品 对于新冠肺炎的治疗策略，了解其细胞类型和分子机制是至关重要的 调节冠状病毒感染、组织繁殖和宿主免疫反应。正如最近报道的那样，两者 SARS-CoV和SARS-CoV-2利用宿主ACE2受体蛋白和蛋白酶TMPRSS2获得细胞 进入。高通量单细胞RNA测序(scRNA-seq)及转座酶可及性检测 染色质(scatac-seq)现在允许我们以前所未有的分辨率询问细胞类型和细胞状态， 这导致了肺组织生物学的突破性发现，包括我们的实验室和人类细胞 共同表达ACE2和TMPRSS2的鼻腔和肺上皮细胞类型的Atlas最新调查与 疾病表型。有报道称，患有慢性呼吸道疾病的个人更多 易患新冠肺炎重症疾病。我们建议利用我们在肺部生物学方面的专业知识，单细胞 新冠肺炎慢性呼吸道疾病患者在西奈山的肺组织分析和独特获取 疾病并存以确定介导新冠肺炎病的细胞类型和调控机制 由于SARS-CoV-2感染的易感性、繁殖和与宿主免疫反应的相互作用。 为了实现这一目标，我们将进行scRNA-seq、scatac-seq和多个 25~30例新冠肺炎合并慢性阻塞性肺疾病患者感染和非感染肺区分析 尸检后的疾病共病。单元格分辨率数据将使我们能够表征 SARS-CoV-2感染细胞及其周围基质和免疫微环境的研究进展 助力发展新冠肺炎大病。来自匹配肺区的SCATAC-SEQ数据分析 将确定驱动相关表达程序的关键转录因子和调控机制 病毒感染、宿主免疫反应和严重疾病易感性。最后，配体-受体的整合 配对表达和空间转录信息将以更高的分辨率和规模阐明细胞如何- 冠状病毒感染后细胞相互作用和组织病理改变。细胞的单细胞特性 感染的细胞类型、免疫反应和调节机制将提高我们对病毒的理解-- 宿主相互作用与慢性呼吸道疾病患者新冠肺炎严重疾病易感性的关系。这 反过来，将提供对发现新的治疗靶点的机械洞察力，这些靶点特别有益 新冠肺炎患者有既往呼吸道疾病。

PROJECT SUMMARY The new coronavirus (SARS-CoV-2) and associated disease (COVID-19) is a global threat to worldwide economies and public health due to its highly contagious nature and rapid spread. To develop optimal strategies for treatment of COVID-19, it is critical to understand the cell types and molecular mechanisms that mediate coronavirus infection, tissue propagation, and host immune response. As recently reported, both SARS-CoV and SARS-CoV-2 use the host ACE2 receptor protein and protease TMPRSS2 to gain cellular entry. High-throughput single-cell RNA-sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin (scATAC-seq) now allow us to interrogate cell types and cell states at unprecedented resolution, which has led to groundbreaking discoveries in lung tissue biology, including our lab’s and the Human Cell Atlas recent survey of nasal and lung epithelial cell types that co-express ACE2 and TMPRSS2 consistent with disease phenotype. It has been reported that individuals suffering from chronic respiratory diseases are more susceptible to COVID-19 severe disease. We propose to leverage our expertise in lung biology, single-cell analysis, and unique access to lung tissue at Mount Sinai from COVID-19 patients with chronic respiratory disease comorbidities to define the cell types and regulatory mechanisms that mediate COVID-19 disease susceptibility due to SARS-CoV-2 infection, propagation and interplay with the host immune response. Towards this goal, we will perform scRNA-seq, scATAC-seq, and spatial transcriptomic sequencing of multiple infected and non-infected lung regions in 25-30 patients with COVID-19 and chronic obstructive pulmonary disease comorbidity following autopsy. The single-cell resolution data will allow us to characterize the repertoire of SARS-CoV-2 infected cell and surrounding stromal and immune microenvironment and how they contribute to developing COVID-19 severe disease. Analysis of scATAC-seq data from matched lung regions will identify the key transcription factors and regulatory mechanisms driving the expression programs related to viral infection, host immune response, and severe disease susceptibility. Finally, integration of ligand-receptor pair expression and spatial transcriptomics information will elucidate at greater resolution and scale how cell- cell interactions and tissue pathology are altered after coronavirus infection. Single-cell characterization of the cell types, immune response, and regulatory mechanisms of infection will improve our understanding of virus- host interactions and COVID-19 severe disease susceptibility in patients with chronic respiratory disease. This will, in turn, provide mechanistic insight towards discovering new therapeutic targets that specifically benefit COVID-19 patients with pre-existing respiratory conditions.