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

• 批准号: 7706862
• 负责人: DALE T UMETSU
• 金额: $ 25.08万
• 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: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706862
• 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; airway hyperresponsiveness; airway inflammation; antimicrobial; base; cell type; clinically relevant; density; improved; killer T cell; microbial; microorganism; novel; pathogen; prevent; respiratory; response

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）细胞如何识别和响应呼吸道粘膜中的微生物。我们以前已经证明，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。尽管已知只有少数微生物激活NKT细胞，但基于强有力的初步数据，我们认为许多肺部微生物，包括肺炎链球菌、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，从而导致先天性和适应性粘膜免疫应答。此外，我们假设，微生物，如少动鞘氨醇单胞菌，是更常见的慢性肺部炎症性疾病患者的气道粘膜比以前认识到的，和主机响应这些以前未被识别的微生物在支气管粘膜可以触发慢性疾病的气道。因此，我们建议确定糖脂从S。肺炎，B. B. cenocepacia和A.因此，证明了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，为了证明这些机制的临床相关性，我们建议检查慢性肺病患者的肺（例如，哮喘）的细菌的存在，使用一种非常敏感的，新型的非培养的16S rRNA PhyloChip微阵列方法，该方法使用大约500，000个探针来检测来自9，000个细菌的16S核糖体RNA签名。令人惊讶的是，初步数据表明，一个高度多样化的复杂的细菌聚生体，包括S。肺炎杆菌和先前未通过基于培养的技术检测到的细菌，如鞘氨醇单胞菌属（Sphingomonasspecies）（表达可激活NKT细胞的糖脂），确实存在于大部分哮喘患者的肺中。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，我们已经产生了令人兴奋的初步数据，这表明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的发展，如哮喘。