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: 10558633
• 负责人: JASON S DEBLEY
• 金额: $ 86.39万
• 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/10558633
• 关键词: Adrenal Cortex Hormones; Adult; Affect; Alleles; Apoptosis; Asthma; Biological Products; Cells; Characteristics; Child; Clinical; Data; Emergency department visit; Epithelial Cells; Epithelium; Frequencies; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genotype; Heterogeneity; Hospitalization; Human; Incidence; Infection; Inflammasome; Inflammation; Inhalation; Interferon Type II; 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64万急诊科就诊， 每年有28万人住院，1400万天缺课。2型(T2)细胞因子驱动 炎症是儿童最常见的哮喘内型(T2-High)，并与 病毒引发的恶化风险。虽然吸入性皮质类固醇(ICS)或 生物制剂减少了许多患者的恶化频率，这些治疗方法是次优的，有数百万 在美国，每年病毒引发的病情恶化。此外，T2炎症的治疗不会改变 哮喘的自然病史和对30%患有T2低哮喘的儿童和成人的有效治疗是 缺乏。病毒感染在哮喘儿童中引发最严重的恶化，其中人鼻病毒(HRV) 是最常见的。已有研究报道哮喘患者存在I型和III型干扰素反应缺陷。 AECS和假设干扰素反应不足易导致病情恶化，然而，这一概念是 有争议的是，其他人没有观察到哮喘AEC对病毒的干扰素反应不足。我们有 观察到AEC干扰素在基线水平或对体外病毒感染的反应中更高的表达与 哮喘供者的肺功能较低。此外，在最近一项关于易加重的纵向研究中 哮喘儿童上皮细胞T2基因模块的基线表达增加和干扰素的表达降低 模组与病毒引发的恶化的时间更短有关。 在我们特征良好的哮喘儿童队列中，我们从他们那里获得支气管血管内皮细胞并进行 使用器官模型的体外机械实验，我们观察到干扰素具有显著的异质性 易加重的血管内皮细胞对HRV和RSV感染的I/III应答，HRV复制增加 哮喘患者。我们最近观察到哮喘AEC产生更多的T2警示分子TSLP和IL-33 对心率变异性的干扰素λ应答最低，而干扰素λ应答最强的血管内皮细胞也最强 产生T2-LOW/NLRP3炎症体相关细胞因子IL-1β和肿瘤坏死因子-α。这些观察结果， 告知我们的全球假设：AEC对HRV的干扰素反应的大小和动力学影响T2-HIGH 和T2-低哮喘内型，具有适度的自限干扰素反应，对限制病毒复制至关重要， 降低恶化风险，抑制T2炎症，而夸大的干扰素反应增强 NLRP3炎症体和T2低细胞因子(IL-1β、肿瘤坏死因子-α)的产生，中性粒细胞和炎症， 气道重塑，肺功能下降。此外，我们还假设， 最近与哮喘有关的病毒传感器IFIH1/MDA5(Rs1990760)与AEC调节失调有关 干扰素对HRV的应答。最后，我们将使用表达hICAM1的人源化小鼠来允许HRV-A感染， 在差异MDA5功能的背景下，为了在体内测试这些途径在HRV-A感染中的作用，T2- 高VS T2-低气道炎症、恶化和气道重塑。