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: 10610419
• 负责人: Michael Bradley Drummond
• 金额: $ 76.09万
• 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/10610419
• 关键词: Acute; Affect; Age; Biological; Biological Markers; Chronic Obstructive Pulmonary Disease; Clinical; Cluster Analysis; Communities; Constitution; Constitutional; Data; Deterioration; Development; Disease susceptibility; Effector Cell; Environment; Fingerprint; Frequencies; Functional disorder; Host Defense; Immune; Immune response; Immunity; Individual; Inflammatory; Inflammatory Response; Innate Immune Response; Knowledge; Link; Lung diseases; Measures; Mediator; Modeling; Mucosal Immunity; Nose; Pattern; Phenotype; 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; disease phenotype; disorder risk; functional status; live attenuated influenza vaccine; microbiome; microbiome composition; nasal microbiome; non-smoker; novel; poor health outcome; 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.

项目总结/摘要 慢性阻塞性肺疾病（COPD）是一种进行性肺部疾病，其特征是频繁的呼吸道感染。 急性恶化发作称为COPD急性加重（AECOPD）。潜在的生物 导致AECOPD的机制和风险特征知之甚少。鼻粘膜环境， 包括炎症状态和鼻微生物组，在宿主防御病毒感染中起作用。 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表征和量化 鼻粘膜免疫环境和微生物组，以及确定鼻功能状态 免疫环境与受控的减毒活流感疫苗（LAIV）接触。我们的整体目标 确定鼻免疫环境变化的免疫改变和功能影响 和存在于频繁AECOPD个体中的微生物组。我们假设功能失调的鼻腔免疫 是常见AECOPD表型的基础，因此提出了AECOPD增加的新机制 风险我们假设这些免疫改变将影响对受控病毒感染的反应， 预测自然发生的AECOPD的过程。我们将定义鼻免疫环境（目标1）， 频繁加重者、罕见加重者和健康非吸烟者的微生物组（目标2），使用聚类 分析以定义常见AECOPD表型的鼻“生物指纹”。通过纵向 评估嵌入在这些目标，我们将定义这些措施的变化在稳定状态， 在AECOPD期间。然后，我们将使用减毒活流感疫苗（LAIV）模型来确定功能性 频繁和不频繁的急性加重期患者呼吸道免疫环境差异的意义 受控病毒攻击（目标3）。成功地完成这些目标将导致第一个严格的 与COPD频繁加重相关的鼻粘膜和微生物组变化的表征， 在一个受控的实验环境中验证这些发现，并提出一个新的假设， 恶化表型由改变的鼻免疫应答和微生物组构成引起。