Modulation of Lung Immune Responses to Viral Infection

调节肺部对病毒感染的免疫反应

基本信息

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
项目类别：
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

项目摘要

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.

修改后的项目摘要/摘要部分严重的 COVID-19 与长期肺部后遗症有关。重症 COVID-19 患者会出现急性呼吸窘迫综合征，随后肺部疾病、持续性严重炎症性肺损伤或纤维化得到缓解。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。在动物模型和人类肺部中，许多免疫细胞群已被证明会导致肺纤维化。最近，在恢复期的 COVID-19 中，T 细胞亚群（如 CD8+ 组织驻留记忆细胞和 CXCR6+CD8+ 细胞）与长期肺部后遗症有关。还有一篇新兴文献表明，新的自身抗体是在急性 COVID-19 早期形成的，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 肺部修复异常的重要因素。将研究之前从重症 COVID-19 患者和因 COVID-19 以外原因导致急性呼吸衰竭的当代对照中收集的气管抽吸物和外周血样本。第一个目标是使用高维流式细胞术表征与肺纤维化相关的免疫细胞亚群。第二个目标是确定 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有关。第三个目标将利用下一代蛋白质组学平台 SomaScan 来检测与 COVID-19 肺损伤和纤维化发展相关的免疫蛋白。这些研究将共同确定 COVID-19 中肺部恢复受损和肺纤维化的关键肺部和循环免疫介质。