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

项目概要/摘要 慢性阻塞性肺疾病（COPD）是一种进行性肺部疾病，其特征是频繁出现 急性恶化的发作称为慢性阻塞性肺病急性加重（AECOPD）。底层生物 人们对 AECOPD 的机制和风险状况了解甚少。鼻粘膜环境， 包括炎症状态和鼻腔微生物群，在宿主防御病毒感染中发挥作用。 对病毒感染的易感性是 AECOPD 的触发因素，也是 COPD 频繁发生的潜在机制。 加剧表型。我们的研究小组已经建立了严格表征和量化的方法 鼻粘膜免疫环境和微生物组，以及确定鼻腔的功能状态 具有受控的减毒活流感疫苗（LAIV）暴露的免疫环境。我们的总体目标 是为了确定鼻免疫环境变化的免疫改变和功能影响 以及经常患有 AECOPD 的个体中存在的微生物组。我们假设鼻免疫功能失调 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，并可能 预测自然发生的 AECOPD 的病程。我们将定义鼻免疫环境（目标 1）和 使用聚类分析频繁加重者、不频繁加重者和健康非吸烟者的微生物组（目标 2） 分析以确定常见 AECOPD 表型的鼻“生物指纹”。通过纵向 这些目标中嵌入的评估，我们将定义这些措施在稳定状态期间的变化，以及 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 频繁和不频繁加重者呼吸免疫环境差异的影响 受控病毒挑战（目标 3）。成功完成这些目标将带来第一个严格的目标 与慢性阻塞性肺病频繁加重相关的鼻粘膜和微生物组变化的特征， 在受控实验环境中验证这些发现，并提出一个新的假设，即频繁的 加重表型是由鼻免疫反应和微生物组成的改变引起的。

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.