Impact of Virome on Microbial Communities in the Respiratory Tract

病毒组对呼吸道微生物群落的影响

• 批准号: 10806485
• 负责人: Jennifer Melinda Bomberger
• 金额: $ 17.22万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10806485
• 关键词: Impact; Virome; Microbial; Communities; Respiratory

SUMMARY/ABSTRACT Respiratory viral infections contribute significantly to the morbidity and progressive decline in lung function experienced by patients with chronic lung diseases, such as cystic fibrosis (CF). Respiratory viral infections account for at least 50% of pulmonary exacerbations of adult CF patients and are linked to worsening of pulmonary function, antibiotic use, prolonged hospitalizations and increased respiratory symptoms. Clinical studies have also linked viral infections with the development of chronic infections, yet the underlying mechanisms are unknown. In this proposal, we will test the novel hypothesis that viral exacerbations alter the microbial composition of the upper and/or lower respiratory tract in CF, affecting both overall community diversity and function and impairing pulmonary function. This study is innovative and exploratory in nature and intended to lay the foundation for future studies to both uncover the molecular mechanisms underlying viral-bacterial interactions in the respiratory tract during chronic lung disease and also inform larger clinical studies that assess the impact of viral exacerbations on disease progression in CF and other chronic lung diseases. In the R61 phase of the award, we will use samples previously collected longitudinally over the course of one year from the sinonasal cavity of CF patients during endoscopic surgery. In Aim 1, we will determine if viral infections of the upper respiratory tract (URT) alter the microbial communities of the URT. In Aim 2, we will investigate potential mechanisms by which viral infections shape the microbial composition of the URT, focusing on skewed innate immune responses and altered nutritional immunity, as well as take an unbiased approach using ribosome profiling to assess functional pathways activated during viral infection that might shift the microbial communities of the URT. The R33 phase will build upon preliminary data and techniques adapted during the R61 phase to assess how viral infections alter the microbiome composition and function throughout the respiratory tract and if these alterations predict pulmonary function. Longitudinal, paired sinonasal and sputum samples will be collected every three months for two years. In Aim 3, we will examine if viral infections shift the microbial communities of the URT or LRT, as well as assess changes in innate immunity or nutritional immunity (i.e. elemental metals analysis) or microbial pathways activated that predict pulmonary function decline during viral infection. This phase will culminate in Aim 4 with mechanistic in vitro studies modeling key microbial interactions or pathways revealed in Aim 3, using our unique polymicrobial infection models with primary sinonasal and bronchial epithelial cells from CF patients. By elucidating mechanisms by which viral infections impact microbial communities in the respiratory tract, our long-term goal is to identify new therapeutic targets for intervention.

摘要/摘要 呼吸道病毒感染极大地促进了肺功能的发病率和进行性下降 患有囊性纤维化(CF)等慢性肺部疾病的患者会经历这种情况。呼吸道病毒感染 至少占成人CF患者肺部恶化的50%，并与 肺功能、抗生素使用、住院时间延长和呼吸道症状增加。临床 研究还将病毒感染与慢性感染的发展联系起来，但潜在的 机制尚不清楚。在这项提议中，我们将测试新的假设，即病毒加剧改变 林木上呼吸道和/或下呼吸道的微生物组成，影响群落的整体多样性 和功能，并损害肺功能。本研究具有创新性和探索性，旨在 为未来的研究奠定基础，既揭示病毒-细菌的分子机制 在慢性肺部疾病期间呼吸道的相互作用，也为评估 病毒加重对慢性肺病和其他慢性肺部疾病疾病进展的影响。 在颁奖的R61阶段，我们将使用之前在一个过程中纵向收集的样本 鼻内窥镜手术中CF患者离开鼻腔一年。在目标1中，我们将确定病毒是否 上呼吸道(URT)感染改变了URT的微生物群落。在目标2中，我们将 研究病毒感染影响城市轨道交通微生物组成的潜在机制，重点 关于扭曲的先天免疫反应和改变的营养免疫，以及采取公正的方法 使用核糖体图谱评估在病毒感染期间激活的功能通路可能会改变 城市轨道交通的微生物群落。 R33阶段将建立在R61阶段采用的初步数据和技术的基础上，以评估 病毒感染如何改变整个呼吸道的微生物群组成和功能？如果这些 改变可以预测肺功能。每隔一年将采集纵向、成对的鼻窦和痰样本 三个月就是两年。在目标3中，我们将研究病毒感染是否改变了 以及评估先天免疫或营养免疫的变化(即元素分析) 或者，在病毒感染期间，被激活的微生物通路预测肺功能下降。这一阶段将 在目标4中使用机制体外研究来模拟关键的微生物相互作用或途径 目的3，使用我们独特的鼻腔和支气管上皮细胞感染模型。 Cf患者。 通过阐明病毒感染影响呼吸道微生物群落的机制， 我们的长期目标是确定新的干预治疗靶点。