Recognition of microbes by NKT cells at the lung mucosal surface

肺粘膜表面NKT细胞对微生物的识别

• 批准号: 7822608
• 负责人: DALE T UMETSU
• 金额: $ 37.75万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822608
• 关键词: Address; Alveolus; Antigens; Area; Aspergillus fumigatus; Asthma; Bacteria; Burkholderia; Cells; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical Research; Complement; Complex; DNA; Data; Deposition; Development; Disease; Endotoxins; Flagella; Glycolipids; Goals; Grant; Host Defense; Immune; Immune response; Immunity; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Response; Lead; Lung; Lung Inflammation; Lung diseases; Methods; Microbe; Molecular; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Patients; Pattern; Pattern recognition receptor; Play; Pulmonary Gas Exchange; Research; Respiratory Mucosa; Respiratory System; Respiratory tract structure; Ribosomal RNA; Role; Sphingomonas; Sterility; Streptococcus pneumoniae; Surface; Techniques; Vaccination; airway hyperresponsiveness; airway inflammation; antimicrobial; base; cell type; improved; killer T cell; microbial; microorganism; novel; pathogen; prevent; public health relevance; respiratory; response

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research, and the specific Challenge Topic, 04-AI-101: Develop novel methods and address key questions in mucosal immunology. The long-term goal of this project is to understand how natural killer T (NKT) cells recognize and respond to microorganisms in the respiratory mucosa. We and others have previously shown that NKT cells in the lungs play a critical role in the development of airway inflammation and asthma. In addition, we have shown that glycolipids from the bacterial species Sphingomonas can directly activate pulmonary NKT cells in mice and induce airway inflammation and airway hyperreactivity (AHR), a cardinal feature of asthma. These results suggest that NKT cells in the lung mucosa may respond to other microorganisms that enter the lung, and that NKT cells could play a previously unsuspected critical role in regulating pulmonary mucosal immune responses. Although the lungs of most patients with asthma are thought to be sterile, we have strong and surprising preliminary data indicating that a highly diverse complex bacterial consortia are in fact present in the lungs of a large fraction of patients with asthma, as detected with an extremely sensitive, novel non-culture based 16S rRNA PhyloChip microarray method. The microorganisms present include Streptococcus pneumoniae, as well as bacteria not previously detected by culture-based techniques, such as Sphingomonas paucimobilis, which express glycolipids that can activate NKT cells. Based on these studies, we suggest that microorganisms are much more common in the airway mucosa of patients with chronic pulmonary inflammatory diseases than previously recognized. Furthermore, while only a few microorganisms are known to activate NKT cells, based on strong preliminary data, we hypothesize that many pulmonary microorganisms, including S. pneumoniae, Burkholderia cenocepacia, Sphingomonas paucimobilis and Aspergillus fumigatus express glycolipids that can activate NKT cells, resulting in innate and adaptive mucosal immune responses. We therefore believe that host responses to common, as well as previously unrecognized, microorganisms in the endobronchial mucosa can trigger chronic diseases in the airways. In this project, we propose to identify glycolipids from S. pneumoniae, B. cenocepacia, and A. fumigatus that can directly activate NKT cells. These studies will demonstrate a specific mechanism by which microorganisms present in the lungs can activate NKT cells and induce AHR, inflammation and asthma. Our studies will greatly expand the fundamental understanding of the types of immune responses that develop against microorganisms present in the respiratory mucosa, and how these responses result in the development of chronic lung diseases, such as asthma. PUBLIC HEALTH RELEVANCE: The results of these studies will have a direct impact on our fundamental understanding of the immune responses that occur in the respiratory mucosa. We propose to understand how a novel cell type, called natural killer T cells, fundamentally regulates innate and adaptive immunity to respiratory microorganisms. These studies will complement additional studies that we are performing, supported by other grants and using a novel, highly sensitive non-culture molecular method, to define the microorganisms that are present in the lungs of patients with chronic lung disease, such as asthma. These results will provide a much greater appreciation and understanding of mucosal immunity to microorganisms present in the respiratory tract, and how these immune responses lead to respiratory inflammation and to the development of chronic lung diseases, such as asthma and COPD.

描述（由申请人提供）：本申请涉及广泛的挑战领域（04）临床研究和特定的挑战主题04-AI-101：开发新方法并解决粘膜免疫学中的关键问题。该项目的长期目标是了解自然杀伤T（NKT）细胞如何识别和响应呼吸道粘膜中的微生物。我们和其他人以前已经表明，肺中的NKT细胞在气道炎症和哮喘的发展中起着关键作用。此外，我们已经表明，来自鞘氨醇单胞菌属的糖脂可以直接激活小鼠肺NKT细胞，并诱导气道炎症和气道高反应性（AHR），这是哮喘的主要特征。这些结果表明，肺粘膜中的NKT细胞可能对进入肺的其他微生物产生反应，并且NKT细胞可能在调节肺粘膜免疫应答中发挥先前未被怀疑的关键作用。尽管大多数哮喘患者的肺部被认为是无菌的，但我们有强有力且令人惊讶的初步数据表明，事实上，很大一部分哮喘患者的肺部存在高度多样化的复杂细菌聚生体，正如用极其敏感的检测到的那样，新型的基于非培养的16 S rRNA PhyloChip微阵列方法。存在的微生物包括肺炎链球菌，以及先前未通过基于培养的技术检测到的细菌，如少动鞘氨醇单胞菌，其表达可激活NKT细胞的糖脂。基于这些研究，我们认为微生物在慢性肺部炎症性疾病患者的气道粘膜中比以前认识到的要常见得多。此外，虽然只有少数微生物已知激活NKT细胞，基于强有力的初步数据，我们假设许多肺部微生物，包括S。肺炎杆菌、新洋葱伯克霍尔德氏菌、少动鞘氨醇单胞菌和烟曲霉表达可激活NKT细胞的糖脂，导致先天性和适应性粘膜免疫应答。因此，我们认为，宿主对支气管粘膜中常见的以及以前未被识别的微生物的反应可以引发气道中的慢性疾病。在这个项目中，我们提出了确定糖脂从S。肺炎克雷伯氏菌（B. pneumoniae）、B. cenocepacia和A.能直接激活NKT细胞。这些研究将证明存在于肺部的微生物可以激活NKT细胞并诱导AHR，炎症和哮喘的特定机制。我们的研究将大大扩展对呼吸道粘膜中存在的微生物的免疫反应类型的基本理解，以及这些反应如何导致慢性肺部疾病（如哮喘）的发展。 公共卫生关系：这些研究的结果将直接影响我们对呼吸道粘膜中发生的免疫反应的基本理解。我们建议了解一种称为自然杀伤T细胞的新型细胞类型如何从根本上调节对呼吸道微生物的先天性和适应性免疫。这些研究将补充我们正在进行的其他研究，这些研究得到了其他赠款的支持，并使用了一种新型的、高度敏感的非培养分子方法，以确定存在于慢性肺部疾病（如哮喘）患者肺部的微生物。这些结果将提供对呼吸道中存在的微生物的粘膜免疫的更大的理解和理解，以及这些免疫反应如何导致呼吸道炎症和慢性肺部疾病（如哮喘和COPD）的发展。