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

• 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
• 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

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次急诊就诊， 每年有28万人住院，1400万人缺课。2型（T2）电机驱动 炎症是儿童中最常见的哮喘内型（T2-高）的特征， 病毒引发的急性加重风险。尽管使用吸入性皮质类固醇（ICS）或 生物制剂降低了许多患者的加重频率，这些治疗是次优的， 此外，T2炎症的治疗不会改变T2炎症的发生率。 哮喘的自然史，以及30%的儿童和成人T2低哮喘的有效治疗方法是 缺乏病毒感染引发哮喘儿童的大多数加重，其中人鼻病毒（HRV） 是最常见的。有些人报道哮喘患者I型和III型干扰素（IFN）应答不足， AECs和假定IFN应答缺陷易使病情加重，然而，这一概念是错误的。 因为其他人没有观察到哮喘AEC对病毒的干扰素应答缺陷。我们有 观察到在基线或对离体病毒感染的应答中更大的AEC IFN表达与 哮喘捐赠者的肺功能较低。此外，在最近的一项关于急性加重倾向的 哮喘儿童T2基因模块的基线上皮表达较高，IFN表达较低 模块与较短的病毒触发急性加重时间相关。 在我们的一组特征明确的哮喘儿童中，我们从他们那里获得支气管AEC，并进行 使用器官型模型的机械离体实验，我们观察到IFN-γ的显著异质性， 对HRV和RSV感染的I/III反应，在易加重的AEC中HRV复制更大 哮喘患者我们最近观察到哮喘AEC产生更多的T2警报素TSLP和IL-33 具有最低IFNλ应答的AEC对HRV的应答，而具有最大IFNλ应答的AEC也具有最大IFNλ应答。 产生T2-low/NLRP 3炎性小体相关细胞因子IL-1β和TNF-α。这些观察， 告知我们的全球假设，AEC IFN对HRV反应的幅度和动力学影响T2-高 和T2-低哮喘内型，具有限制病毒复制所必需的中度自限性IFN应答， 降低恶化风险，抑制T2炎症，而过度的IFN反应增强了T2炎症。 NLRP 3炎性小体和T2低细胞因子（IL-1β、TNF-α）的产生，嗜酸性粒细胞和炎症， 气道重塑和肺功能下降。此外，我们假设，一个共同的多态性， 病毒感受器IFIH 1/MDA 5（rs 1990760），最近与哮喘相关，导致AEC失调 IFN对HRV的反应。最后，我们将使用表达hICAM 1的人源化小鼠来允许HRV-A感染， 在MDA 5功能差异的背景下，为了在体内测试这些途径在HRV-A感染中的作用，T2- 高T2与低T2-气道炎症、恶化和气道重塑。