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640，000次急诊和1400万次 每年都错过上学的日子。病毒感染引发大多数儿童病情加重，其中人类 鼻病毒（HRV）是最常见的。气道上皮细胞在调节 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 呼吸道上皮细胞（AEC）对病毒感染的反应是表达I型和III型干扰素（IFN I/III） 和IFN刺激基因（ISG）。一些人报道了IFN I/III对病毒感染的应答缺陷， 哮喘的AEC，并假设上皮细胞对病毒的IFN应答缺陷易使病情加重， 而其他人没有观察到哮喘和哮喘患者之间AEC IFN对病毒的反应存在差异， 健康的AEC。在我们独特的哮喘儿童和健康儿童队列中，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型培养进行机械实验 模型，我们已经观察到显着的异质性IFN I/III响应HRV和RSV感染。为 例如，在我们的哮喘AEC供体中，我们注意到I/III型IFN高应答与 和较低的供体肺功能，以及不同的亚组的急性发作倾向的哮喘患者， IFN I/III对HRV的反应。AEC IFN I/III对病毒感染的应答中的异源性可解释为： 编码病毒传感器的基因的多态性和/或信号转导途径上游的关键步骤， IFN I和IFN III。我的研究项目的总体目标是了解气道上皮细胞如何 影响哮喘儿童病毒触发的急性发作和气道重塑机制。在 第一个目标是，使用来自哮喘儿童的原代细胞，我们将检验我们的假设， 编码病毒传感器的基因，和/或IFN应答上游信号转导途径中的关键步骤， 哮喘患儿AEC对HRV感染的IFN I/III反应的异质性。在 第二个目的，我们将前瞻性地跟踪一组哮喘儿童，以验证我们的假设，即缺乏 AEC对HRV的IFN I/III应答与病毒触发的AEC急性加重的发生率较高相关 捐助者。在最后的目标，我们将测试我们的假设，过高的IFN I/III反应的哮喘， AEC对HRV的影响与AEC供体的肺功能下降有关，我们将询问潜在的 过高的IFN I/III应答可能促进肺增殖和活化的机制 基质细胞在我的研究项目中进行的研究和原发性气道上皮细胞的独特资源 来自临床上表现良好的哮喘儿童的细胞为年轻人提供了一个特殊的训练环境， 研究人员致力于以患者为导向的机械研究的职业生涯，以学习转化研究 研究呼吸道上皮细胞在小儿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.