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

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.

123 456 789 1101 1123 1145 1167 1189 2201 2223 2245 2267 2289 摘要 尽管越来越多的努力来了解微生物群在气道疾病中的作用， 微生物群落生态失调对慢性炎症的影响仍然难以捉摸。慢性鼻窦炎（CRS）是一种 这是美国一个严重的健康问题，每年造成的损失高达650亿美元，影响了美国16%的人口。 美国人口。CRS患者经常出现肺部合并症，这表明 导致上呼吸道和下呼吸道炎症的常见潜在病理生理机制， 被称为统一航空概念。在这个建议中，我们旨在了解上层和下层的作用， 气道微生物群在CRS和哮喘患者中驱动并行免疫应答。哮喘是一 与CRS有很强临床和流行病学关联的常见肺部疾病：20%- 60%的CRS鼻息肉患者患有哮喘。据报道， 然而，CRS患者的鼻窦和哮喘患者的肺中的微生物组或宿主免疫应答， 这些地点没有同时进行检查。该提案的目的是建立一个 通过对细菌和真菌微生物组进行测序，分析宿主免疫 反应，并通过体外实验，旨在确定混合物种培养物中的细菌代谢产物 导致II型炎症的基因支持统一气道的概念，我们的初步数据显示， CRS伴哮喘和并发2型哮喘患者上、下呼吸道的微生物群落 气道部位共有炎症。为了扩大这些研究，我们将使用一个集成的多组学 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应答（有或没有 哮喘）和健康的人，我们已经在过去四年中存入。通过这些分析，我们将 能够推断出导致同时发生的上、下呼吸道慢性炎症的生态关系， 呼吸道疾病在第二个目标中，我们将确定病原微生物群落是否以及如何驱动 或加剧体外气道炎症反应。我们将描述CRS/哮喘的代谢组学特征- 患者，并确认这些代谢产物是混合物种生物膜培养物中的微生物来源。以确定 与宿主的相互作用，我们将致敏外周血树突状细胞（DC）与CRS-哮喘相关 代谢物，然后将DC与幼稚T细胞共培养并定量T细胞分化。这项研究将有助于 我们对统一气道疾病中上下气道轴的理解，并最终导致 旨在操纵上呼吸道微生物组以治疗并发鼻窦和肺的治疗学 疾病