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.

项目概要美国儿童哮喘恶化导致 64 万人次到急诊室就诊，1400 万人次就诊每年都缺课。病毒感染会引发儿童的大部分病情恶化，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、气道重塑反应和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表达 I 型和 III 型干扰素 (IFN I/III) 和干扰素刺激基因（ISG）。有些人报告说，IFN I/III 对病毒感染的反应不足哮喘 AEC 并假设上皮 IFN 对病毒的反应不足容易导致病情加重，而其他人尚未观察到哮喘患者和哮喘患者之间 AEC IFN 对病毒的反应存在差异。健康的 AEC。在我们独特的一组具有明确特征的哮喘和健康儿童中，我们从他们那里获得了支气管和鼻 AEC 并使用气液界面器官培养进行机械实验模型中，我们观察到 IFN I/III 对 HRV 和 RSV 感染的反应存在显着异质性。为了例如，在我们的哮喘 AEC 捐赠者中，我们注意到高 I/III IFN 反应之间的关联和较低的供体肺功能，以及具有缺陷的易于恶化的哮喘患者的不同亚组 IFN I/III 对 HRV 的反应。 AEC IFN I/III 对病毒感染反应的异质性可以解释为编码病毒传感器的基因多态性和/或病毒上游信号转导途径的关键步骤干扰素 I 和 III。我的研究计划的总体目标是了解气道上皮反应如何影响哮喘儿童病毒引发的病情加重和气道重塑机制。在第一个目标，使用来自哮喘儿童的原代细胞，我们将检验我们的假设，即多态性编码病毒传感器的基因，和/或 IFN 反应上游信号转导途径的关键步骤，导致哮喘儿童 AEC 对 HRV 感染的 IFN I/III 反应的异质性。在第二个目标，我们将前瞻性地跟踪一组哮喘儿童，以检验我们的假设： AEC IFN I/III 对 HRV 的反应与 AEC 中病毒触发的恶化发生率较高相关捐助者。在最终目标中，我们将检验我们的假设，即哮喘患者对 IFN I/III 的反应过高 AEC 与 HRV 的关系与 AEC 供体中的肺功能下降有关，我们将探讨潜在的可能性过高的 IFN I/III 反应可能促进肺细胞增殖和活化的机制基质细胞。我的研究计划中进行的研究和初级气道上皮的独特资源来自临床特征明确的哮喘儿童的细胞为年轻人提供了特殊的训练环境致力于以患者为中心的机械研究的研究人员学习转化研究研究气道上皮在儿科肺部疾病和病毒感染中的作用的技术。