Fungal Exposure and the Respiratory Tract Microbiome

真菌暴露和呼吸道微生物组

• 批准号: 8606033
• 负责人: Christopher M Evans
• 金额: $ 30.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606033
• 关键词: Address; Aerosols; Affect; Alveolar; Animal Model; Antifungal Agents; Applications Grants; Area; Aspergillus; Aspergillus oryzae; Asthma; Automobile Driving; Bacteria; Biology; Breathing; Child; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Complex; Data; Deposition; Development; Disease; Distal; Economics; Environment; Environmental Exposure; Environmental Health; Exposure to; Extrinsic allergic alveolitis; Extrinsic asthma; Fostering; Funding Mechanisms; Future; Genetic Polymorphism; Genus staphylococcus; Glycoproteins; Growth; Health; Health Care Costs; Histopathology; Host Defense; Human; Immune; Immunity; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation Exposure; Investigation; Knockout Mice; Link; Lower respiratory tract structure; Lung; Lung diseases; MUC5AC gene; MUC5B gene; Measures; Modeling; Molds; Mucins; Mucociliary Clearance; Mucositis; Mucous Membrane; Mucous body substance; Mus; Nature; Nose; Occupational; Organism; Oropharyngeal; Particulate; Pathogenesis; Pathology; Patients; Personal Satisfaction; Play; Population; Predisposition; Process; Production; Regulation; Relative (related person); Research; Research Proposals; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Rest; Role; Saline; Sinus; Site; Staphylococcus aureus; Surface; Taxon; Testing; Tissues; Toxicant exposure; Tracheobronchial; Viral; Wild Type Mouse; Work; aerosolized; airway hyperresponsiveness; allergic airway disease; antimicrobial; base; body system; design; environmental agent; in vivo; interest; man; microbial; microbiome; mouse model; novel; overexpression; particle; pathogen; public health relevance; respiratory; response; toxicant

DESCRIPTION (provided by applicant): The respiratory system is a central host-environment interface that is exposed to billions of particles and pathogens daily. Airway mucus is critical fo eliminating deposited environmental agents and limiting pathogen accumulation through a process called mucociliary clearance (MCC). Mucus production and composition are dramatically altered in numerous lung diseases. Recent studies have identified changes in the lung microbiome in asthma and COPD, but direct links between altered MCC function and changes in the respiratory microbiome have not been tested. In this exploratory grant proposal, mechanisms by which fungal toxicant exposure elicits changes will be identified in the upper and lower respiratory tract microbiomes along with the functional consequences of these changes. This work focuses on the major macromolecular components of airway mucus - mucin glycoproteins encoded by the MUC5AC and MUC5B genes. Recent studies in patients with asthma and COPD show that alterations in mucus production are related to differential regulation of MUC5AC (which goes up) and MUC5B (which remains stably expressed or goes down). To address whether mucins determine respiratory microbial diversity, Muc5ac and Muc5b knockout mice were recently generated. In the absence of an inflammatory challenge, Muc5b (but not Muc5ac) deficiency causes spontaneous lethal infections marked by acquisition of pulmonary Staphylococcus aureus infection. Thus, Muc5b is essential for controlling homeostatic and pathological microbial populations in the lungs. Here, the intent is to accomplish the primary purpose of this RFA - to test "how environmental exposures impact the composition and/or function of the microbiome" - in mouse models of respiratory inflammation. Aspergillus fungal exposure is a major cause of asthma exacerbations and several types of hypersensitivity pneumonitis, a related occupational lung disease. In preliminary studies, wild type mice exposed to an aerosol Aspergillus oryzae extract (AOE) show inflammation, increased Muc5ac, and reduced Muc5b expression similar to that seen in humans with asthma. Thus, it is hypothesized that AOE-induced changes in respiratory microbiome composition are dependent upon Muc5b expression levels and that these changes affect disease pathology and susceptibility to opportunistic pathogen infection. To test this, wild type mice will be exposed to aerosolized AOE. Changes will be measured in the upper and lower airway microbiota, and we will assess changes in inflammation, histopathology, and susceptibility to S. aureus. These data will be compared to that seen in Muc5b deficient and Muc5b overexpressing mice. Collectively, these studies will be used to develop a framework for designing and analyzing subsequent investigations in mice and in humans. MUC5B expression varies significantly in humans, and common genetic polymorphisms significantly regulate its expression. In addition treatments such as inhaled hypertonic saline enhance MCC effectively. Thus, successful completion of the proposed studies may significantly impact human health in the near-term.

描述(申请人提供)：呼吸系统是一个中心宿主-环境界面，每天暴露在数十亿颗粒和病原体中。呼吸道粘液是通过粘液纤毛清除(MCC)过程清除沉积的环境物质和限制病原体积累的关键。在许多肺部疾病中，粘液的产生和组成都发生了显著的变化。最近的研究已经确认了哮喘和COPD患者肺微生物组的变化，但MCC功能变化和呼吸道微生物组变化之间的直接联系尚未得到检验。在这项探索性拨款提案中，将确定真菌毒物暴露引起上呼吸道和下呼吸道微生物群变化的机制以及这些变化的功能后果。本工作主要研究由MUC5AC和MUC5B基因编码的呼吸道粘液糖蛋白的主要大分子成分。最近对哮喘和COPD患者的研究表明，粘液产生的变化与MUC5AC(上调)和MUC5B(保持稳定表达或下调)的不同调节有关。为了解决粘蛋白是否决定呼吸道微生物多样性，最近产生了Muc5ac和MUC5B基因敲除小鼠。在没有炎症性挑战的情况下，MUC5B(但不是Muc5ac)缺乏会导致以获得肺部金黄色葡萄球菌感染为特征的自发性致死性感染。因此，MUC5B对于控制肺部的动态平衡和病理微生物种群是必不可少的。在这里，目的是实现这种RFA的主要目的--在呼吸道炎症的小鼠模型中测试“环境暴露如何影响微生物组的组成和/或功能”。曲霉真菌暴露是哮喘恶化和几种类型的过敏性肺炎的主要原因，过敏性肺炎是一种相关的职业性肺部疾病。在初步研究中，暴露于米曲霉提取物(AOE)气雾剂的野生型小鼠表现出炎症，增加了Muc5ac，并降低了MUC5B的表达，类似于人类哮喘患者。因此，假设AOE诱导的呼吸道微生物组组成的变化依赖于MUC5B的表达水平，并且这些变化影响疾病病理和对机会性病原体感染的易感性。为了测试这一点，野生型老鼠将暴露在 雾化AOE。将测量上呼吸道和下呼吸道微生物区系的变化，我们将评估炎症、组织病理学和金黄色葡萄球菌敏感性的变化。这些数据将与MUC5B缺陷和MUC5B过度表达的小鼠进行比较。总的来说，这些研究将被用来开发一个框架，用于设计和分析随后在小鼠和人类身上进行的研究。MUC5B在人类中的表达差异很大，常见的遗传多态显著调节其表达。此外，吸入高渗盐水等治疗可有效提高MCC。因此，成功完成拟议的研究可能在短期内对人类健康产生重大影响。