Determining the Role of the Upper and Lower Airway Microbiota as Drivers of Concomitant Inflammatory Responses in patients with Chronic Rhinosinusitis and Asthma

确定上呼吸道和下呼吸道微生物群作为慢性鼻窦炎和哮喘患者伴随炎症反应驱动因素的作用

• 批准号: 9813180
• 负责人: James Gregory Caporaso
• 金额: $ 46.85万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813180
• 关键词: Accounting; Address; Affect; Airway Disease; Asthma; Automobile Driving; Biological Assay; Biological Markers; Categories; Cells; Chronic; Classification; Clinical; Clinical Microbiology; Coculture Techniques; Communities; Comorbidity; Complex; Data; Dendritic Cells; Diagnosis; Disease; Ecology; Epidemiology; Epithelial; Functional disorder; Gender; Gene Expression; Genes; Goals; Health; Health Care Costs; Healthcare; Heterogeneity; Human; Immune response; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Investigation; Lead; Link; Liquid substance; Lung; Lung diseases; Machine Learning; Mediating; Medical; Microbe; Modality; Mucous Membrane; Nasal Polyps; Operative Surgical Procedures; Pathogenicity; Patients; Phenotype; Polyps; Population; Public Health; Quality of life; Reporting; Resolution; Role; Sampling; Sinus; Site; Structure; Surface; Symptoms; T cell differentiation; T-Lymphocyte; Therapeutic; United States; Work; airway inflammation; asthmatic; asthmatic airway; asthmatic patient; bacterial community; bacteriome; base; chronic rhinosinusitis; clinically relevant; cohort; cost; dysbiosis; experimental study; fungal microbiota; host-associated microbial communities; host-microbe interactions; immune function; improved; in vivo; inflammatory milieu; metabolome; metabolomics; microbial; microbial community; microbial host; microbiome; microbiota; microorganism interaction; mucosal microbiota; multiple omics; mycobiome; nasal microbiome; pathobiont; patient response; peripheral blood; polarized cell; polymicrobial biofilm; predictive modeling; rRNA Genes; respiratory microbiome; respiratory microbiota; Accounting; Address; Affect; Airway Disease; Asthma; Automobile Driving; Biological Assay; Biological Markers; Categories; Cells; Chronic; Classification; Clinical; Clinical Microbiology; Coculture Techniques; Communities; Comorbidity; Complex; Data; Dendritic Cells; Diagnosis; Disease; Ecology; Epidemiology; Epithelial; Functional disorder; Gender; Gene Expression; Genes; Goals; Health; Health Care Costs; Healthcare; Heterogeneity; Human; Immune response; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Investigation; Lead; Link; Liquid substance; Lung; Lung diseases; Machine Learning; Mediating; Medical; Microbe; Modality; Mucous Membrane; Nasal Polyps; Operative Surgical Procedures; Pathogenicity; Patients; Phenotype; Polyps; Population; Public Health; Quality of life; Reporting; Resolution; Role; Sampling; Sinus; Site; Structure; Surface; Symptoms; T cell differentiation; T-Lymphocyte; Therapeutic; United States; Work; airway inflammation; asthmatic; asthmatic airway; asthmatic patient; bacterial community; bacteriome; base; chronic rhinosinusitis; clinically relevant; cohort; cost; dysbiosis; experimental study; fungal microbiota; host-associated microbial communities; host-microbe interactions; immune function; improved; in vivo; inflammatory milieu; metabolome; metabolomics; microbial; microbial community; microbial host; microbiome; microbiota; microorganism interaction; mucosal microbiota; multiple omics; mycobiome; nasal microbiome; pathobiont; patient response; peripheral blood; polarized cell; polymicrobial biofilm; predictive modeling; rRNA Genes; respiratory microbiome; respiratory microbiota

123 456 789 1101 1123 1145 1167 1189 2201 2223 2245 2267 2289 ABSTRACT Despite growing efforts to understand the role of the microbiota in airway disease, mechanisms that link microbial community dysbiosis to chronic inflammation remain elusive. Chronic rhinosinusitis (CRS) is a significant health problem in the United States, costing up to $65 billion each year and affecting up to 16% of the US population. CRS patients frequently present with pulmonary comorbidities suggesting that there are common underlying pathophysiologic mechanisms that contribute to upper and lower airway inflammation, known as the unified airways concept. In this proposal, we aim to understand the role of the upper and lower airway microbiota in driving concurrent immune responses in patients with CRS and asthma. Asthma is a common pulmonary disease that has strong clinical and epidemiological associations with CRS: Between 20%- 60% of CRS patients with nasal polyps have asthma. Dysbiotic microbial communities have been reported in sinuses of CRS patients and in the lungs of asthmatics, however, the microbiome or host immune response of these sites have not been examined in parallel. The goal of this proposal is to establish the existence of an upper-lower airway axis by sequencing the bacterial and fungal microbiome, profiling the host immune response, and through in vitro experiments that aim to identify bacterial metabolites in mixed-species culture that drive type-2 inflammation. Supporting the concept of a unified airway, our preliminary data show dysbiotic microbial communities in the upper and lower airways of CRS patients with asthma and concurrent type-2 inflammation shared across the airway sites. To expand these studies, we will use an integrated multi-omics approach to investigate the fundamental basis of microbiome structure and function in the context of the immune response of patient-matched upper and lower airway samples from CRS patients (with or without asthma) and healthy individuals that we have banked over the past four years. From these analyses, we will be able to infer the ecological relationships that contribute to chronic inflammation in concurrent upper and lower airway disease. In the second aim, we will determine whether and how pathogenic microbial communities drive or exacerbate airway inflammatory responses in vitro. We will characterize the metabolome in CRS/Asthma- patients and confirm these metabolites are of microbial origin in mixed species biofilm culture. To determine interaction with the host, we will sensitize peripheral blood dendritic cells (DCs) with CRS-Asthma associated metabolites, then co-culture DCs with naïve T cells and quantify T cell differentiation. This study will contribute to our understanding of the upper-lower airway axis in unified airway disease and will ultimately lead to therapeutics aimed a manipulating the upper airway microbiome for treating concurrent sinus and lung disease.

一二三 456 789 1101 1123 1145 1167 1189 2201 2223 2245 2267 2289 抽象的 尽管越来越努力了解微生物群在气道疾病中的作用，但与 微生物群落营养不良对慢性炎症仍然难以捉摸。慢性鼻孔炎（CRS）是 美国重大健康问题，每年耗资高达650亿美元，影响多达16％ 美国人口。 CRS患者经常出现肺合并症，表明有 有助于上下气道注射的常见潜在病理生理机制， 称为统一航空概念。在此提案中，我们旨在了解上层和下部的作用 气道微生物群在CRS和哮喘患者中驱动并发免疫复杂。哮喘是一个 常见的肺疾病与CRS具有强烈的临床和流行病学关联：20％ - 60％的鼻息肉患者患有哮喘。据报道 然而 这些站点尚未并行检查。该提议的目的是建立一个 通过对细菌和真菌微生物组进行测序，将宿主免疫分析，通过测序上低较低的气道轴 反应，以及通过体外实验，旨在鉴定混合物种培养物中的细菌代谢产物 那个驱动器2型注射。支持统一气道的概念，我们的初步数据表明失调不足 CRS患者上下气道中的微生物群落患有哮喘和类型-2 在气道站点共享炎症。为了扩展这些研究，我们将使用综合的多媒体 研究微生物组结构和功能的基本基础的方法 来自CRS患者的患者匹配的上和下气道样品的免疫反应（有或没有 在过去的四年中，我们已经养了哮喘和健康的人。从这些分析中，我们将 可以推断出有助于并发上下的慢性炎症的生态关系 气道疾病。在第二个目标中，我们将确定是否以及如何以及如何驱动致病性微生物群落 或在体外加剧气道炎症反应。我们将表征CRS/哮喘中的代谢组 患者并确认这些代谢产物在混合物种生物膜培养中具有微生物起源。确定 与宿主的相互作用，我们会感觉到外周血树突状细胞（DC）与CRS-雅典相关的 代谢产物，然后与幼稚的T细胞共培养DC并量化T细胞分化。这项研究将有助于 为了理解统一气道疾病中高低气道轴的理解，最终将导致 治疗剂的旨在操纵上呼吸道微生物组，以治疗并发鼻窦和肺 疾病。