Sputum Microbial-Immune Relationships to Clinical Phenotype in Asthma and COPD

迫切需要确定导致临床表现和反应不同的生物学因素。 用于治疗哮喘和慢性阻塞性肺疾病(COPD)。越来越多的人认识到 疾病进展、结果和症状负担的异质性，以及 呼吸道微生物群和呼吸道免疫环境之间存在重要联系的证据 继续突出新的调查途径。目前的证据支持区分哮喘患者 通过两种免疫表型-广义地说，那些2型细胞因子谱和痰数量升高的人 嗜酸性粒细胞(T2-High)和非嗜酸性粒细胞(T2-Low)。虽然描述COPD表型的免疫学特征 不太清楚的是，最近的证据表明，除了传统的T2-低表型外，还有一个T2-高的亚型。我们的 总体假设是，下呼吸道微生物区系组成和功能的不同模式区分了T2- 哮喘的高和低T2-低炎症，在T2-低的表型中存在共同的微生物特征 哮喘和慢性阻塞性肺疾病。因此，本项目的目标是1)确定呼吸道微生物组特征 与T2-低哮喘表型相关，以及2)定义与以下相关的呼吸道微生物群特征 T2-低炎症背景下哮喘和COPD严重程度的临床特征。在目标1中，我们 建议确定呼吸道微生物区系的特定成员及其功能特征 使用来自3个样本的样本在哮喘中与T2-低炎症和T2-高炎症相关的可能性 独立的成人哮喘队列。我们的工作假设是1)组成和功能特征 痰微生物区系，特别是涉及伽马变形杆菌的成员，在不同的 T2-Low哮喘与T2-Low哮喘的临床特征相关。2)非细菌成员 的痰微生物组，特别是真菌，在T2-高哮喘中有不同程度的丰富，并与 T2偏高人群哮喘的临床特点。在目标2中，我们建议确定具体的 呼吸道微生物区系的成员及其功能潜力的特征 使用来自这两种疾病的联合数据，在哮喘和COPD中，T2-低与T2-高炎症。 我们的工作假设是T2-低哮喘和T2-低COPD都与相似的成分和 痰细菌微生物群的功能特征，尤其涉及变形杆菌成员。这 该项目将极大地促进我们目前对呼吸道微生物临床意义的理解 T2-Low哮喘的生物失调，以及呼吸道微生物区系对COPD表型的贡献。它还将 提供对病毒、真菌和功能与哮喘和COPD表型的关联的新见解。

There is a critical need to identify biological factors that underlie differences in clinical presentation and response to treatment in asthma and chronic obstructive pulmonary disease (COPD). The growing recognition of heterogeneity in disease progression, outcomes, and burden of symptoms in combination with mounting evidence of an important link between the airway microbiome and the immunologic milieu of the airways continues to highlight new avenues of investigation. Current evidence supports distinguishing asthma patients by two immunological phenotypes –broadly, those with elevated type 2 cytokine profiles and numbers of sputum eosinophils (T2-high) and those without (T2-low). While immunologic features that delineate COPD phenotypes are less clear, recent evidence suggests a T2-high subtype in addition to the traditionally T2-low phenotype. Our overall hypothesis is that distinct patterns of lower airway microbiota composition and function differentiate T2- high and T2-low inflammation in asthma, with shared microbial features present in the T2-low phenotypes of asthma and COPD.Therefore, the objectives of this project are to 1) Define airway microbiome features associated with T2-low asthma phenotype, and 2) Define features of the airway microbiome associated with clinical characteristics of asthma and COPD severity within the context of T2-low inflammation. In Aim 1, we propose to determine the specific members of the airway microbiota and features of their functional potential that associate with T2-low vs. T2-high inflammation in asthma using samples from 3 independent adult asthma cohorts. Our working hypotheses are 1) Compositional and functional features of sputum microbiota, particularly involving members of the Gammaproteobacteria, are differentially enriched in T2-low asthma and associate with clinical characteristics of asthma in T2-low subjects. 2)Non-bacterial members of the sputum microbiome, particularly fungi, are differentially enriched in T2-high asthma and associate with clinical characteristics of asthma in T2-high subjects. In Aim 2, we propose to determine the specific members of the airway microbiota and features of their functional potential that differentially associate with T2-low vs. T2-high inflammation in both asthma and COPD using combined data from both diseases. Our working hypothesis is that both T2-low asthma and T2-low COPD associate with similar compositional and functional features of the sputum bacterial microbiome, involving Proteobacteria members in particular. This project will significantly advance our current understanding of the clinical implications of airway microbial dysbiosis in T2-low asthma, and the contributions of the airway microbiota to COPD phenotype. It will also provide novel insight into the viral, fungal, and functional associations with asthma and COPD phenotype.