Dysregulated asthmatic epithelial interferon responses to viruses drive exacerbation, T2 inflammation, and airway remodeling

哮喘上皮干扰素对病毒的反应失调会导致病情加重、T2 炎症和气道重塑

基本信息

批准号：
10446799
负责人：
JASON S DEBLEY
金额：
$ 91.94万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446799
关键词：
Adrenal Cortex Hormones Adult Affect Alleles Apoptosis Asthma Biological Products Cells Characteristics Child Clinical Data Emergency department visit Epithelial Epithelial Cells Frequencies Gene Expression Genes Genetic Genetic Polymorphism Genotype Heterogeneity Hospitalization Human Incidence Infection Inflammasome Inflammation Inhalation Interferons Interleukin-1 beta Kinetics Knock-out Longitudinal Studies Minor Modeling Mouse Strains Natural History Pathway interactions Patients Prevalence Production Proteins Quantitative Trait Loci Reporting Respiratory Syncytial Virus Infections Rhinovirus Rhinovirus infection Risk Role Schools System TNF gene TNFSF10 gene TSLP gene Testing Time Viral Virus Virus Diseases Virus Replication Work airway epithelium airway inflammation airway remodeling asthma exacerbation asthmatic asthmatic airway cohort cytokine effective therapy experimental study functional decline gain of function genomic locus human model humanized mouse in vivo in vivo evaluation insight mouse model neutrophil novel novel therapeutics pulmonary function pulmonary function decline response sensor transcriptomics

项目摘要

Project Summary: Asthma exacerbations among U.S children result in 640,000 emergency department visits, 280,000 hospitalizations, and 14 million missed school days annually. Type 2 (T2) cytokine-driven inflammation characterizes the most common asthma endotype in children (T2-high) and is associated with viral-triggered exacerbation risk. Although treatment of T2-high asthma with inhaled corticosteroids (ICS) or biologics reduces exacerbation frequency in many patients, these treatments are suboptimal with millions of viral-triggered exacerbations annually in the U.S. Furthermore, treatment of T2 inflammation does not alter the natural history of asthma, and effective treatments for the 30% of children and adults with T2-low asthma are lacking. Viral infections trigger most exacerbations in asthmatic children, of which human rhinoviruses (HRV) are the most common. Some have reported deficient type I and III interferon (IFN) responses by asthmatic AECs and postulated that deficient IFN responses predispose to exacerbations, however, this concept is controversial as others have not observed deficient IFN responses to viruses by asthmatic AECs. We have observed that greater AEC IFN expression at baseline or in response to ex vivo viral infection is associated with lower lung function in asthmatic donors. Furthermore, in a recent longitudinal study of exacerbation-prone asthmatic children higher baseline epithelial expression of a T2 gene module and lower expression of an IFN module were associated with a shorter time to viral-triggered exacerbation. In our cohort of well characterized asthmatic children, from whom we obtain bronchial AECs and conduct mechanistic ex vivo experiments using organotypic models, we have observed marked heterogeneity in IFN I/III responses to HRV and RSV infection, with greater HRV replication in AECs from exacerbation-prone asthmatics. We recently observed greater production of the T2 alarmins TSLP and IL-33 by asthmatic AECs with the lowest IFNλ responses to HRV, while AECs with the greatest IFNλ responses also had the greatest production of T2-low/NLRP3 inflammasome-associated cytokines IL-1β and TNF-α. These observations, inform our global hypotheses that the magnitude and kinetics of AEC IFN responses to HRV influence T2-high and T2-low asthma endotypes, with moderate self-limited IFN responses essential to limit viral replication, reduce exacerbation risk, and dampen T2 inflammation, while exaggerated IFN responses enhance the NLRP3 inflammasome and production of T2-low cytokines (IL-1β, TNF-α), neutrophilic and inflammation, airway remodeling, and lung function decline. Furthermore, we hypothesize that a common polymorphism in the viral sensor IFIH1/MDA5 (rs1990760), recently associated with asthma, contributes to dysregulated AEC IFN responses to HRV. Finally, we will use a humanized mouse expressing hICAM1 to allow HRV-A infection, in the context of differential MDA5 function, to test in vivo the role of these pathways in HRV-A infection, T2- high vs. T2-low airway inflammation, exacerbation, and airway remodeling.

项目摘要：美国儿童哮喘恶化导致 640,000 人次到急诊室就诊，每年有 280,000 人住院，1400 万人因 2 型 (T2) 细胞因子缺课。炎症是儿童最常见哮喘内型（T2-高）的特征，并且与尽管用吸入皮质类固醇（ICS）或 T2 高哮喘治疗有病毒引发的恶化风险。生物制剂可降低许多患者的病情恶化频率，但这些治疗方法对于数百万患者来说并不是最理想的在美国，每年都有病毒引发的病情加重。此外，T2 炎症的治疗不会改变哮喘的自然史，以及对 30% 患有 T2 低哮喘的儿童和成人的有效治疗病毒感染会引发哮喘儿童的大多数病情恶化，其中人类鼻病毒（HRV）。一些报告称哮喘患者 I 型和 III 型干扰素 (IFN) 反应不足。 AEC 并假设 IFN 反应不足会导致病情加重，然而，这一概念是由于其他人尚未观察到哮喘 AEC 对病毒的干扰素反应不足，因此存在争议。观察到基线时或响应离体病毒感染时 AEC IFN 表达较高是相关的此外，在最近的一项针对哮喘发作倾向的纵向研究中。哮喘儿童 T2 基因模块的基线上皮表达较高，而 IFN 表达较低模块与病毒触发的恶化时间较短相关。在我们的一组特征明确的哮喘儿童中，我们从他们身上获得了支气管 AEC 并进行了使用器官模型进行离体机制实验，我们观察到 IFN 具有显着的异质性对 HRV 和 RSV 感染的 I/III 反应，在易恶化的 AEC 中 HRV 复制较多我们最近观察到哮喘 AEC 产生更多的 T2 警报素 TSLP 和 IL-33。对 HRV 的 IFNλ 反应最低，而 IFNλ 反应最大的 AEC 也具有最大的 T2-low/NLRP3 炎性体相关细胞因子 IL-1β 和 TNF-α 的产生。告知我们的总体假设，即 AEC IFN 对 HRV 反应的幅度和动力学影响 T2-high 和 T2 低哮喘内型，具有适度的自限性 IFN 反应，对于限制病毒复制至关重要，降低恶化风险，抑制 T2 炎症，而过度的 IFN 反应则增强 NLRP3 炎性体和 T2 低细胞因子（IL-1β、TNF-α）、中性粒细胞和炎症的产生，此外，我们还发现了常见的多态性。最近与哮喘相关的病毒传感器 IFIH1/MDA5 (rs1990760) 会导致 AEC 失调最后，我们将使用表达 hICAM1 的人源化小鼠来允许 HRV-A 感染，在MDA5功能差异的背景下，测试这些途径在HRV-A感染、T2-体内的作用高与 T2-低气道炎症、恶化和气道重塑。