Modulation of Lung Immune Responses to Viral Infection

调节肺部对病毒感染的免疫反应

• 批准号: 10413443
• 负责人: Anna Karolina Palucka
• 金额: $ 49.83万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-02 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413443
• 关键词: 2019-nCoV; 3-Dimensional; Acute; Address; Administrative Supplement; Adult; Affect; Age; Alternative Splicing; Antigens; Antiviral Response; Autoimmune Diseases; Award; B-Lymphocytes; Bacteria; Biology; Biomedical Engineering; Blood Cells; COVID-19; COVID-19 patient; Cell Line; Cell model; Cell physiology; Cells; Cellular biology; Child; Childhood; Childhood Asthma; Clinical; Code; Cohort Effect; Communication; Complement; Complex; Computational Biology; Computer Analysis; Coronavirus; Data Set; Dendritic Cells; Dimensions; Disease; Environment; Environmental Risk Factor; Epithelial; Epithelial Cells; Family; Funding; Future; Generations; Genes; Genetic Transcription; Genomics; Goals; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Immunology; Immunology procedure; Individual; Infant; Infection; Inflammation; Influenza; Interferon Type I; Interferons; Interleukin-1; Invaded; Leukocytes; Long COVID; Lung; Lung diseases; Lymphocyte; Lymphoid Cell; Malignant neoplasm of lung; Messenger RNA; Molecular; Mucous Membrane; Natural Immunity; Parents; Pathway interactions; Patients; Pediatric cohort; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Production; Protein Isoforms; Proteins; Proteomics; Public Health; RNA; RNA Splicing; Recording of previous events; Research; Research Project Grants; Respiratory syncytial virus; Ribonucleoproteins; SARS-CoV-2 infection; Sampling; Severity of illness; Shapes; Small Nuclear RNA; Specificity; Spliceosomes; Structure; Structure of parenchyma of lung; Surface; Systemic Lupus Erythematosus; T cell response; T-Lymphocyte; Technology; The Jackson Laboratory; Tissues; Transcript; Vaccines; Viral Load result; Viral Respiratory Tract Infection; Virus; Virus Diseases; Work; adaptive immune response; adaptive immunity; antiviral immunity; base; bioprinting; cell type; cohort; comorbidity; coronavirus disease; design; detection method; follow-up; human model; human tissue; immune activation; immune function; imprint; improved outcome; influenzavirus; innovative technologies; insight; lung microbiome; mRNA Precursor; mRNA sequencing; microbiome; microbiota; monocyte; multidisciplinary; novel; pathogen; pediatric patients; programs; proteogenomics; respiratory virus; response; sensor; single-cell RNA sequencing; symptomatic COVID-19; technology development; tool; transcriptome; transcriptome sequencing; tumor; virtual

Modified Project Summary/Abstract Section Severe COVID-19 has been associated with long term pulmonary sequelae. Patients with severe COVID-19 develop acute respiratory distress syndrome and this can be followed by resolution of lung disease, persistent severe inflammatory lung injury, or fibrosis. The immune system, particularly at mucosal sites, is critical to resolve ongoing inflammatory responses but also to promote tissue repair. COVID-19 provides a unique opportunity to define how mucosal immunity mediates tissue damage, recovery, or aberrant fibrotic repair. Numerous immune cell populations have been shown to contribute to lung fibrosis in animal models and in human lungs. Most recently in convalescent COVID-19, T cell subsets, like CD8+ tissue resident memory cells and CXCR6+CD8+ cells have been associated with long term pulmonary sequelae. There is also an emerging literature that novel autoantibodies are formed early in acute COVID-19 particularly in hospitalized patients. Autoimmune disease is a known risk factor for the development of pulmonary fibrosis. This suggests a possible link between autoreactivity in COVID-19 and pulmonary sequelae of disease. In this study, the immune cell populations, proteins, and autoreactive changes will be studied to determine the important factors that contribute to aberrant lung repair in COVID-19. Previously collected tracheal aspirate and peripheral blood samples from patients with severe COVID-19 and contemporary controls with acute respiratory failure due to causes other than COVID-19 will be studied. The first aim will characterize immune cell subsets that associated with pulmonary fibrosis using high dimensional flow cytometry. The second aim will identify autoantibodies and autoreactive T cell populations that are present in the airway in patients with COVID-19 and whether development of autoreactivity associates with impaired pulmonary recovery. The third aim will utilize a next generation proteomics platform, SomaScan, to detect immune proteins that associate with the development of lung injury and fibrosis in COVID-19. Together, these studies will establish the key lung and circulating immune mediators of impaired pulmonary recovery and pulmonary fibrosis in COVID-19.

修改项目摘要/摘要部分 严重的COVID-19与长期的肺部后遗症有关。重度COVID-19患者会出现急性呼吸窘迫综合征，随后可能会出现肺部疾病消退、持续性重度炎性肺损伤或纤维化。免疫系统，特别是粘膜部位的免疫系统，对于解决持续的炎症反应以及促进组织修复至关重要。COVID-19提供了一个独特的机会来定义粘膜免疫如何介导组织损伤、恢复或异常纤维化修复。在动物模型和人肺中，许多免疫细胞群体已被证明有助于肺纤维化。最近在COVID-19的恢复期，T细胞亚群，如CD 8+组织驻留记忆细胞和CXCR 6 + CD 8+细胞，与长期肺部后遗症有关。还有一项新的文献表明，新型自身抗体在急性COVID-19早期形成，特别是在住院患者中。自身免疫性疾病是肺纤维化发展的已知危险因素。这表明COVID-19的自身反应性与疾病的肺部后遗症之间可能存在联系。在这项研究中，将研究免疫细胞群、蛋白质和自身反应性变化，以确定导致COVID-19异常肺修复的重要因素。将研究之前从严重COVID-19患者和同期对照组中采集的因COVID-19以外原因导致急性呼吸衰竭的气管抽吸物和外周血样本。第一个目的是利用流式细胞术对肺纤维化相关的免疫细胞亚群进行分析。第二个目标将确定COVID-19患者气道中存在的自身抗体和自身反应性T细胞群，以及自身反应性的发展是否与肺部恢复受损相关。第三个目标将利用下一代蛋白质组学平台SomaScan检测与COVID-19肺损伤和纤维化发展相关的免疫蛋白。总之，这些研究将确定COVID-19中肺恢复受损和肺纤维化的关键肺和循环免疫介质。