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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要新的冠状病毒（SARS-COV-2）和相关疾病（Covid-19）是全球对全球的威胁经济和公共卫生由于其高度传染性和快速传播而引起的公共卫生。发展最佳 COVID-19的治疗策略，了解细胞类型和分子机制至关重要介导冠状病毒感染，组织繁殖和宿主免疫响应。正如最近报道的那样，这两个 SARS-COV和SARS-COV-2使用宿主ACE2受体蛋白和蛋白TMPRSS2获得细胞入口。高通量单细胞RNA - 序列（SCRNA-SEQ）和转座酶可访问的测定染色质（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开创性发现，包括我们的实验室和人类细胞 Atlas最近对鼻和肺上皮细胞类型的调查，这些细胞类型与ACE2和TMPRSS2一致疾病表型。据报道，患有慢性呼吸系统疾病的人更多容易受到199种严重疾病的影响。我们建议利用我们在肺部生物学，单细胞的专业知识分析，并从199例慢性呼吸道的Covid-19患者的西奈山上进入肺组织疾病合并症，以定义介导COVID-19疾病的细胞类型和调节机制由于SARS-COV-2感染，传播和与宿主免疫响应的相互作用引起的敏感性。为了实现这一目标，我们将执行多个的SCRNA-SEQ，SCATAC-SEQ和空间转录组测序 25-30例COVID-19患者和慢性阻塞性肺部感染和未感染的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感染细胞以及周围的基质和免疫微环境以及它们如何有助于开发共同疾病的严重疾病。分析来自匹配的肺部区域的SCATAC-SEQ数据将确定关键的转录因素和调节机制，驱动与病毒感染，宿主免疫反应和严重的疾病敏感性。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大的分辨率阐明，并扩展细胞的方式冠状病毒感染后细胞相互作用和组织病理学会改变。单细胞表征细胞类型，免疫响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共同疾病易感性。这反过来，将为发现新的治疗靶标提供机械洞察力 COVID-19患者患有呼吸系统疾病的患者。