NKT cells recognize and respond to microbes at mucosal surfaces

NKT 细胞识别粘膜表面的微生物并对其做出反应

基本信息

批准号：
7897764
负责人：
DALE T UMETSU
金额：
$ 19.45万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-22 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897764
关键词：
Adrenal Cortex Hormones Alveolus Antigens Aspergillus fumigatus Aspirate substance Asthma Bacteria Biology Breathing Burkholderia Cells Chronic Chronic Disease Chronic Obstructive Airway Disease Chronic lung disease Complex DNA Data Deposition Development Disease Effector Cell Endotoxins Flagella Gastroesophageal reflux disease Glycolipids Goals Host Defense Immune Immune response Immunity Immunology Individual Infection Inflammation Inflammatory Inflammatory Response Lead Lipid Biochemistry Lung Lung Inflammation Lung diseases Methods Microbe Microbiology Molecular Mucosal Immune Responses Mucosal Immunity Mucositis Mucous Membrane Mus Pathogenesis Patients Pattern Pattern recognition receptor Play Pneumonia Pulmonary Gas Exchange RNA, Ribosomal, 16S Research Research Personnel Respiratory Mucosa Respiratory System Respiratory tract structure Ribosomal RNA Role Specimen Sphingomonas Sterility Streptococcus pneumoniae Surface Symptoms Techniques Vaccination adaptive immunity airway hyperresponsiveness airway inflammation antimicrobial base cell type clinically relevant density improved killer T cell microbial microorganism novel pathogen prevent respiratory response

项目摘要

DESCRIPTION (provided by applicant): 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 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 only a few microorganisms are known to activate NKT cells, based on strong preliminary data, we believe that many pulmonary microorganisms, including Streptococcus pneumoniae, Burkholderia cenocepacia, Sphingomonas paucimobilis and Aspergillus fumigatus express glycolipids that can activate NKT cells, resulting in innate and adaptive mucosal immune responses. Furthermore, we hypothesize that microorganisms such as Sphingomonas paucimobilis, are much more common in the airway mucosa of patients with chronic pulmonary inflammatory diseases than previously recognized, and that host responses to these previously unrecognized microorganisms in the endobronchial mucosa can trigger chronic diseases in the airways. We therefore propose to identify glycolipids from S. pneumoniae, B. cenocepacia, and A. fumigatus that can directly activate NKT cells, thus demonstrating a specific mechanism by which these microorganisms can activate NKT cells and induce AHR, inflammation and asthma. Further, to demonstrate the clinical relevance of such mechanisms, we propose to examine the lungs of patients with chronic lung disease (e.g., asthma) for the presence of bacteria, using an extremely sensitive, novel non-culture based 16S rRNA PhyloChip microarray method, which uses approximately 500,000 probes to detect the 16S ribosomal RNA signatures from 9,000 bacteria. Surprisingly, preliminary data indicate that a highly diverse complex bacterial consortia, including S. pneumoniae, and bacteria not previously detected by cultured based techniques, such as Sphingomonas species (expressing glycolipids that can activate NKT cells), are indeed present in the lungs of a large fraction of patients with asthma. We have assembled an outstanding team of investigators, including experts in lung biology, lipid biochemistry, microbiology and immunology. Using very novel techniques, we have generated exciting preliminary data, which suggest that 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.

描述（由申请人提供）：该项目的长期目标是了解自然杀伤 T (NKT) 细胞如何识别呼吸道粘膜中的微生物并对其做出反应。我们之前已经证明，肺部的 NKT 细胞在气道炎症和哮喘的发展中发挥着关键作用。此外，我们还发现，来自鞘氨醇单胞菌细菌的糖脂可以直接激活小鼠的肺部 NKT 细胞，并诱导气道炎症和气道高反应性 (AHR)，这是哮喘的一个主要特征。这些结果表明，肺粘膜中的 NKT 细胞可能会对进入肺部的其他微生物做出反应，并且 NKT 细胞可能在调节肺粘膜免疫反应中发挥以前未曾预料到的关键作用。尽管已知只有少数微生物能够激活 NKT 细胞，但基于强有力的初步数据，我们相信许多肺部微生物，包括肺炎链球菌、新洋葱伯克霍尔德菌、少动鞘氨醇单胞菌和烟曲霉都表达可以激活 NKT 细胞的糖脂，从而产生先天性和适应性的糖脂。粘膜免疫反应。此外，我们假设诸如少动鞘氨醇单胞菌等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更为常见，并且宿主对支气管内粘膜中这些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。因此，我们建议从肺炎链球菌、新洋葱伯克霍尔德菌和烟曲霉中鉴定出可以直接激活NKT细胞的糖脂，从而证明这些微生物可以激活NKT细胞并诱导AHR、炎症和哮喘的特定机制。此外，为了证明此类机制的临床相关性，我们建议使用极其灵敏、新型非培养的 16S rRNA PhyloChip 微阵列方法检查慢性肺病（例如哮喘）患者的肺部是否存在细菌，它使用大约 500,000 个探针来检测 9,000 种细菌的 16S 核糖体 RNA 特征。令人惊讶的是，初步数据表明，高度多样化的复杂细菌群落，包括肺炎链球菌，以及以前未通过培养技术检测到的细菌，例如鞘氨醇单胞菌（表达可以激活 NKT 细胞的糖脂），确实存在于肺中。很大一部分患者患有哮喘。我们组建了一支优秀的研究团队，包括肺生物学、脂质生物化学、微生物学和免疫学方面的专家。使用非常新颖的技术，我们已经生成了令人兴奋的初步数据，这表明我们的研究将极大地扩展对针对呼吸道粘膜中存在的微生物产生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疾病的发展疾病，例如哮喘。