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

解读慢性呼吸道疾病患者COVID-19重症易感性的细胞机制

• 批准号: 10185342
• 负责人: Alexander Minchev Tsankov
• 金额: $ 83.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10185342
• 关键词: 2019-nCoV; ACE2; Angiotensin Receptor; Antibodies; Antibody Diversity; Atlases; Automobile Driving; Autopsy; Biological Assay; Biology; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 susceptibility; COVID-19 treatment; Cell Communication; Cells; Cellular Assay; Chromatin; Chronic; Chronic Obstructive Airway Disease; Collaborations; Collection; Complementary DNA; Computer Analysis; Computer Models; Coronavirus; Coronavirus Infections; Data; Disease; Disease susceptibility; Distal; Epigenetic Process; Epithelial Cells; Gene Expression; Genetic Transcription; Genetic Variation; Genomics; Goals; Histologic; Human; Immune; Immune response; Immune system; Incidence; Individual; Infection; Ligands; Link; Location; Lung; Lung diseases; Measurement; Mediating; Mediator of activation protein; Molecular; Nature; Nose; Nucleic Acid Regulatory Sequences; Nucleotides; Organ; Other Genetics; Pathology; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Positioning Attribute; Protein Isoforms; Public Health; RNA; Regulation; Regulator Genes; Reporting; Research; Resolution; SARS coronavirus; SARS-CoV-2 genome; SARS-CoV-2 infection; Sampling; Serine Protease; Severities; Structure of parenchyma of lung; Surface; Surveys; T-Cell Receptor; TMPRSS2 gene; Technology; Tissues; Transcript; Transposase; Treatment Protocols; United States; Viral; Virus; Virus Diseases; cell type; co-infection; cohort; comorbidity; cytokine; data integration; disease phenotype; genetic profiling; high risk; human coronavirus; improved; insight; new therapeutic target; novel coronavirus; novel therapeutics; programs; receptor; recruit; respiratory; response; severe COVID-19; single cell analysis; single-cell RNA sequencing; transcription factor; transcriptomics; treatment strategy; tumor-immune system interactions; virus host interaction; whole genome

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.

项目概要 新型冠状病毒 (SARS-CoV-2) 和相关疾病 (COVID-19) 对全世界构成全球性威胁 由于其高度传染性和快速传播，对经济和公共卫生造成了影响。制定最优 对于治疗 COVID-19 的策略，了解其细胞类型和分子机制至关重要 介导冠状病毒感染、组织传播和宿主免疫反应。据最近报道，双方 SARS-CoV 和 SARS-CoV-2 使用宿主 ACE2 受体蛋白和蛋白酶 TMPRSS2 来获得细胞 入口。高通量单细胞 RNA 测序 (scRNA-seq) 和转座酶可及性检测 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 Atlas 最近对共表达 ACE2 和 TMPRSS2 的鼻和肺上皮细胞类型的调查与 疾病表型。据报道，患有慢性呼吸道疾病的人较多 易患 COVID-19 严重疾病。我们建议利用我们在肺生物学、单细胞 分析，以及在西奈山对患有慢性呼吸道疾病的 COVID-19 患者的肺组织进行独特的获取 疾病合并症来定义介导 COVID-19 疾病的细胞类型和调节机制 由于 SARS-CoV-2 感染、传播以及与宿主免疫反应的相互作用而导致的易感性。 为了实现这一目标，我们将对多个样本进行 scRNA-seq、scATAC-seq 和空间转录组测序 25-30 名 COVID-19 和慢性阻塞性肺疾病患者的感染和未感染肺部区域 尸检后的疾病合并症。单细胞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所有组成部分以及它们如何 有助于发展 COVID-19 严重疾病。对匹配肺部区域的 scATAC-seq 数据进行分析 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组学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学发生改变。单细胞表征 细胞类型、免疫反应和感染的调节机制将提高我们对病毒的理解 慢性呼吸道疾病患者的宿主相互作用和 COVID-19 严重疾病易感性。这 反过来，将为发现特别有益的新治疗靶点提供机制见解 已有呼吸道疾病的 COVID-19 患者。