The Role of Nasal Mucosal Immunity and Microbiome on the Frequent Exacerbation Phenotype of COPD

鼻粘膜免疫和微生物组对 COPD 频繁恶化表型的作用

• 批准号: 10403429
• 负责人: Michael Bradley Drummond
• 金额: $ 74.69万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-08 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403429
• 关键词: Acute; Affect; Age; Biological; Biological Markers; Chronic Obstructive Pulmonary Disease; Clinical; Cluster Analysis; Communities; Constitution; Data; Deterioration; Development; Effector Cell; Environment; Fingerprint; Frequencies; Functional disorder; Health; Host Defense; Immune; Immune response; Immunity; Individual; Inflammatory; Inflammatory Response; Innate Immune Response; Knowledge; Link; Lung diseases; Measures; Mediator of activation protein; Modeling; Mucosal Immunity; Nose; Outcome; Pattern; Phenotype; Play; Population; Positioning Attribute; Predisposition; Recurrence; Research; Respiratory Signs and Symptoms; Risk; Role; Sampling; Severities; Structure; Structure of mucous membrane of nose; Symptoms; Variant; Viral; Viral Respiratory Tract Infection; Viral load measurement; Virus Diseases; Virus Replication; airway inflammation; clinically relevant; cytokine; functional status; live attenuated influenza vaccine; microbiome; microbiome composition; nasal microbiome; non-smoker; novel; respiratory; respiratory microbiome; response; trait

PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) is a progressive pulmonary disease characterized by frequent episodes of acute deterioration termed acute exacerbations of COPD (AECOPD). The underlying biological mechanisms and risk profiles contributing to AECOPD are poorly understood. The nasal mucosal environment, including the inflammatory state and nasal microbiome, play a role in host defenses against viral infections. Susceptibility to viral infections, a trigger of AECOPD, is a potential mechanism for the COPD frequent exacerbator phenotype. Our research group has established approaches to rigorously characterize and quantify the nasal mucosal immune environment and microbiome, as well as determine the functional status of the nasal immune environment with a controlled Live Attenuated Influenza Vaccine (LAIV) exposure. Our overall objective is to determine the immune alterations and functional implications of changes in the nasal immune environment and microbiome present in individuals with frequent AECOPD. We hypothesize that dysfunctional nasal immunity underlies the frequent AECOPD phenotype and therefore presents a novel mechanism of increased AECOPD risk. We hypothesize that these immune alterations will impact responses to controlled viral infection and could predict the course of naturally occurring AECOPD. We will define the nasal immune environment (Aim 1) and microbiome (Aim 2) of frequent exacerbators, infrequent exacerbators, and healthy non-smokers, using cluster analyses to define the nasal “biological fingerprint” of the frequent AECOPD phenotype. Through longitudinal assessments embedded in these Aims we will define the variations of these measures during stable state and during AECOPD. We will then use a Live Attenuated Influenza Vaccine (LAIV) model to determine the functional implications of differences in the respiratory immune environment of frequent and infrequent exacerbators during a controlled viral challenge (Aim 3). Successful completion of these aims will lead to the first rigorous characterization of the nasal mucosal and microbiome changes associated with frequent exacerbators of COPD, validate these findings in a controlled experimental setting, and advance a novel hypothesis that the frequent exacerbator phenotype arises from altered nasal immune responses and microbiome constitution.

项目摘要/摘要 慢性阻塞性肺疾病(COPD)是一种进展性肺部疾病，其特点是 急性加重发作称为慢性阻塞性肺疾病急性加重(AECOPD)。潜在的生物学 对AECOPD的致病机制和风险特征了解甚少。鼻腔粘膜环境， 包括炎症状态和鼻部微生物群，在宿主抵御病毒感染方面发挥作用。 对病毒感染的易感性是AECOPD的触发因素，是COPD频繁发生的潜在机制 加重表型。我们的研究小组已经建立了严格的表征和量化的方法 鼻腔粘膜免疫环境和微生物群，以及决定鼻腔功能状态 受控的流感减毒活疫苗(LAIV)暴露的免疫环境。我们的总体目标 是为了确定鼻部免疫环境变化的免疫变化和功能影响 和微生物群存在于AECOPD频繁的个体中。我们假设鼻腔免疫功能失调 是AECOPD频繁表型的基础，因此提出了AECOPD增加的新机制 风险。我们推测，这些免疫变化将影响对受控病毒感染的反应，并可能 预测自然发生的AECOPD的进程。我们将定义鼻腔免疫环境(目标1)和 经常加重者、不经常加重者和健康非吸烟者的微生物组(目标2)，使用CLUSTER 分析以确定频繁的AECOPD表型的鼻部“生物指纹”。通过纵向 在这些目标中嵌入的评估，我们将定义这些措施在稳定状态和 在AECOPD期间。然后我们将使用减毒活流感疫苗(LAIV)模型来确定功能 急性加重期频繁和罕见患者呼吸道免疫环境差异的意义 受控病毒挑战(目标3)。这些目标的成功实现将导致第一个严格的 与慢性阻塞性肺疾病频繁加重相关的鼻黏膜和微生物群变化的特征， 在受控实验环境中验证这些发现，并提出一个新的假设 鼻腔免疫反应和微生物群结构的改变引起了恶化的表型。