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

项目摘要 美国儿童哮喘恶化导致64万人次到急诊科就诊，1400万人次 每年的缺课天数。病毒感染引发了儿童的大部分病情恶化，其中人类 鼻病毒(HRV)是最常见的。呼吸道上皮起着重要的调节作用。 炎症、呼吸道重塑反应和对感染的先天免疫反应。最引人注目的 呼吸道上皮细胞对病毒感染的反应是表达I型和III型干扰素(干扰素I/III) 和干扰素刺激基因(ISG)。一些人报告说，干扰素I/III对病毒感染的反应不足 哮喘的血管内皮细胞，并假设上皮细胞对病毒的干扰素反应不足易导致病情恶化， 而其他人则没有观察到哮喘和哮喘患者对病毒的AEC-干扰素反应的差异 健康的AEC。在我们独特的哮喘和健康儿童队列中，我们从他们那里获得 并利用气-液-界面器官培养进行机械实验 模型中，我们观察到干扰素I/III对HRV和RSV感染的反应具有显著的异质性。为 例如，在我们的哮喘AEC捐赠者中，我们注意到高I/III型干扰素应答之间的关联 供者肺功能较低，以及易加重的哮喘患者的不同亚组 干扰素I/III对心率变异性的反应。AEC对病毒感染的干扰素I/III反应的异质性可以用以下方式解释 病毒感受器编码基因的多态性和/或信号转导途径上游的关键步骤 干扰素I和III。我的研究计划的总体目标是了解呼吸道上皮细胞如何反应 影响哮喘儿童的病毒触发的病情加重和呼吸道重塑机制。在 第一个目标是，使用哮喘儿童的原代细胞，我们将检验我们的假设，即 编码病毒传感器的基因，和/或干扰素反应上游信号转导途径的关键步骤， 导致哮喘儿童AECs感染HRV的干扰素I/III反应的异质性。在 第二个目标是，我们将前瞻性地跟踪一组哮喘儿童，以检验我们的假设 AEC干扰素I/III对HRV的反应与AEC中病毒触发的恶化的发生率更高相关 捐赠者。在最终目标中，我们将检验我们的假设，即哮喘患者对干扰素I/III的反应过高 AEC供者的AECS到HRV与肺功能下降有关，我们将询问潜在的 过高的干扰素I/III应答促进肺细胞增殖和活化的机制 基质细胞。在我的研究计划和独特的资源的初级呼吸道上皮进行的研究 来自临床特征良好的哮喘儿童的细胞为年轻儿童提供了一个特殊的训练环境 研究人员致力于以病人为中心的机械化研究，学习翻译研究 探讨呼吸道上皮在儿童肺部疾病和病毒感染中的作用。

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.