Clinical Impacts of Heterogeneous Interferon Responses to Viral Infection by Asthmatic Airway Epithelium

异质干扰素对哮喘气道上皮病毒感染反应的临床影响

基本信息

批准号：
10265757
负责人：
JASON S DEBLEY
金额：
$ 6.72万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265757
关键词：
Adrenal Cortex Hormones Air Asthma Biological Biological Models Cell Culture Techniques Cell Line Cell model Cells Child Childhood Childhood Asthma Clinical Code Emergency department visit Environment Epithelial Epithelial Cells Fibroblasts Frequencies Gene Expression Genes Genetic Polymorphism Goals Heterogeneity Hospitalization Human Incidence Infection Inflammation Inhalation Innate Immune Response Interferons Learning Liquid substance Lung Lung diseases Modeling Morbidity - disease rate Myofibroblast Natural History Nose Pathogenesis Patients Phenotype Play Primary Infection Regulation Reporting Research Research Personnel Research Technics Resources Respiratory Syncytial Virus Infections Rhinovirus Rhinovirus infection Risk Role Schools Series Signal Transduction Pathway Stromal Cells Subgroup Techniques Testing Time Training Translational Research Viral Virus Virus Diseases Virus Replication airway epithelium airway remodeling asthma exacerbation asthmatic asthmatic airway asthmatic patient base career cohort cost cytokine experimental study functional decline loss of function patient oriented patient oriented research prevent programs prospective pulmonary function pulmonary function decline response sensor translational study

项目摘要

Project Summary Asthma exacerbations among U.S children result in 640,000 emergency department visits and 14 million missed school days annually. Viral infections trigger the majority of exacerbations in children, of which human rhinoviruses (HRV) are the most common. The airway epithelium plays central roles in regulating inflammation, airway remodeling responses, and innate immune responses to infection. The most striking response of airway epithelial cells (AECs) to viral infection is expression of type I and III interferons (IFN I/III) and IFN stimulated genes (ISG). Some have reported deficient IFN I/III responses to viral infection by asthmatic AECs and postulated that deficient epithelial IFN responses to viruses predispose to exacerbations, whereas others have not observed differences in AEC IFN responses to viruses between asthmatic and healthy AECs. In our unique cohort of well characterized asthmatic and healthy children, from whom we obtain bronchial and nasal AECs and conduct mechanistic experiments using air-liquid-interface organotypic culture models, we have observed significant heterogeneity in IFN I/III responses to HRV and RSV infection. For example, among our asthmatic AEC donors we have noted associations between high type I/III IFN responses and lower donor lung function, as well as distinct subgroups of exacerbation prone asthmatics with deficient IFN I/III responses to HRV. Heterogeneity in AEC IFN I/III responses to viral infections may be explained by polymorphisms in genes coding for viral sensors and/or key steps in signal transduction pathways upstream of IFN I and III. The overall goal my research program is to understand how airway epithelial responses influence viral-triggered exacerbations and airway remodeling mechanisms in asthmatic children. In the first aim, using primary cells from children with asthma we will test our hypothesis that polymorphisms in genes coding for viral sensors, and/or key steps in signal transduction pathways upstream of IFN responses, contribute to heterogeneity in IFN I/III responses to HRV infection by AECs from asthmatic children. In the second aim, we will prospectively follow a cohort of asthmatic children to test our hypothesis that deficient AEC IFN I/III responses to HRV are associated with a greater incidence of viral-triggered exacerbations in AEC donors. In the final aim, we will test our hypothesis that excessively high IFN I/III responses by asthmatic AECs to HRV are associated with lung function decline among AEC donors, and we will interrogate potential mechanisms whereby excessively high IFN I/III responses may promote proliferation and activation of lung stromal cells. The studies conducted in my research program and unique resource of primary airway epithelial cells from clinically well characterized asthmatic children provide an exceptional training environment for young investigators dedicated to a career in mechanistic patient-oriented research to learn translational research techniques to investigate the role of the airway epithelium in pediatric lung diseases and viral infection.

项目摘要美国儿童中的哮喘恶化导致640,000个急诊室就诊和1400万每年错过上学的日子。病毒感染引发了儿童的大部分加重，其中人类鼻病毒（HRV）是最常见的。气道上皮在调节中起着核心作用炎症，气道重塑反应以及对感染的先天免疫反应。最引人注目的气道上皮细胞（AEC）对病毒感染的反应是I型和III干扰素的表达（IFN I/III）和IFN刺激基因（ISG）。有些人报告说，IFN I/III对病毒感染的反应不足哮喘AEC，并假设缺乏上皮的IFN对病毒的反应易于加剧，而其他人则没有观察到哮喘和健康的AEC。在我们独特的哮喘和健康的孩子中，我们从中获得了支气管和鼻腔AEC并使用空气 - 界面器官型培养物进行机械实验模型，我们观察到IFN I/III对HRV和RSV感染的反应中的显着异质性。为了例如，在我们哮喘的AEC供体中，我们注意到高I/III IFN响应之间的关联和较低 IFN I/III对HRV的响应。 AEC IFN I/III对病毒感染的异质性可能由编码病毒传感器和/或信号转导途径中的关键步骤的基因中的多态性 IFN I和III。我的研究计划的总体目标是了解气道上皮反应哮喘儿童影响病毒触发的加重和气道重塑机制。在首先，使用哮喘儿童的主要细胞，我们将测试我们的假设，即多态性编码病毒传感器的基因和/或IFN响应上游信号转导途径的关键步骤，在IFN I/III对HRV感染的反应中有助于哮喘儿童对HRV感染的异质性。在第二个目的，我们将前瞻性地跟随一群哮喘儿童来检验我们的假设 AEC IFN I/III对HRV的响应与AEC病毒触发加重的发生率更大有关捐助者。在最终目标中，我们将测试我们的假设，即哮喘的IFN I/III反应过高到HRV的AEC与AEC捐助者之间的肺功能下降有关，我们将询问潜力 IFN I/III反应过高的机制可能会促进肺的增殖和激活基质细胞。在我的研究计划中进行的研究和主要气道上皮的独特资源临床表征哮喘儿童的细胞为年轻人提供了出色的训练环境研究人员致力于机械性的以患者为导向的研究，以学习翻译研究研究气道上皮在小儿肺部疾病和病毒感染中的作用的技术。