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
基本信息
- 批准号:7822608
- 负责人:
- 金额:$ 37.75万
- 依托单位:
- 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:2009-09-01 至 2011-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlveolusAntigensAreaAspergillus fumigatusAsthmaBacteriaBurkholderiaCellsChronicChronic DiseaseChronic Obstructive Airway DiseaseChronic lung diseaseClinical ResearchComplementComplexDNADataDepositionDevelopmentDiseaseEndotoxinsFlagellaGlycolipidsGoalsGrantHost DefenseImmuneImmune responseImmunityImmunologyIndividualInflammationInflammatoryInflammatory ResponseLeadLungLung InflammationLung diseasesMethodsMicrobeMolecularMucosal Immune ResponsesMucosal ImmunityMucous MembraneMusPatientsPatternPattern recognition receptorPlayPulmonary Gas ExchangeResearchRespiratory MucosaRespiratory SystemRespiratory tract structureRibosomal RNARoleSphingomonasSterilityStreptococcus pneumoniaeSurfaceTechniquesVaccinationairway hyperresponsivenessairway inflammationantimicrobialbasecell typeimprovedkiller T cellmicrobialmicroorganismnovelpathogenpreventpublic health relevancerespiratoryresponse
项目摘要
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,以及具体的挑战主题 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) 细胞如何识别呼吸道粘膜中的微生物并对其做出反应。我们和其他人之前已经证明,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,高度多样化的复杂细菌群落实际上存在于很大一部分哮喘患者的肺部,正如用极端的方法检测到的那样。灵敏、新颖的非培养 16S rRNA PhyloChip 微阵列方法。存在的微生物包括肺炎链球菌,以及以前通过基于培养的技术未检测到的细菌,例如少动鞘氨醇单胞菌,其表达可以激活 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更为常见。此外,虽然已知只有少数微生物可以激活 NKT 细胞,但基于强有力的初步数据,我们假设许多肺部微生物,包括肺炎链球菌、新洋葱伯克霍尔德杆菌、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,从而导致先天性和适应性粘膜免疫反应。因此,我们认为宿主对支气管内粘膜中常见的以及以前未被识别的微生物的反应可能引发气道的慢性疾病。在这个项目中,我们建议从肺炎链球菌、新洋葱伯克霍尔德杆菌和烟曲霉中鉴定出可以直接激活 NKT 细胞的糖脂。这些研究将证明肺部微生物激活 NKT 细胞并诱导 AHR、炎症和哮喘的特定机制。我们的研究将极大地扩展对针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(例如哮喘)的发展。
公共卫生相关性: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拨款的支持,并使用一种新颖的、高度敏感的非培养分子方法来定义慢性肺病(例如哮喘)患者肺部中存在的微生物。这些结果将使我们对呼吸道中存在的微生物的粘膜免疫以及这些免疫反应如何导致呼吸道炎症和慢性肺部疾病(例如哮喘和慢性阻塞性肺病)的发展有更深入的认识和理解。
项目成果
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{{ truncateString('DALE T UMETSU', 18)}}的其他基金
Targeting innate lymphoid cells during influenza virus-induced asthma
在流感病毒诱发的哮喘期间靶向先天淋巴细胞
- 批准号:
8566307 - 财政年份:2012
- 资助金额:
$ 37.75万 - 项目类别:
Peanut Glycolipid Antigens Activate Natural Killer T Cells Causing Severe Allergy
花生糖脂抗原激活自然杀伤 T 细胞,导致严重过敏
- 批准号:
8044035 - 财政年份:2010
- 资助金额:
$ 37.75万 - 项目类别:
Peanut Glycolipid Antigens Activate Natural Killer T Cells Causing Severe Allergy
花生糖脂抗原激活自然杀伤 T 细胞,导致严重过敏
- 批准号:
7877661 - 财政年份:2010
- 资助金额:
$ 37.75万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 37.75万 - 项目类别:
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:
7935423 - 财政年份:2009
- 资助金额:
$ 37.75万 - 项目类别:
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:
7897764 - 财政年份:2009
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$ 37.75万 - 项目类别:
Mechanisms by which Influenza A Protects Against Asthma
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6913268 - 财政年份:2005
- 资助金额:
$ 37.75万 - 项目类别:
Mechanisms by Which Influenza A Protects Against Asthma
甲型流感预防哮喘的机制
- 批准号:
7449665 - 财政年份:2005
- 资助金额:
$ 37.75万 - 项目类别:
Mechanisms by Which Influenza A Protects Against Asthma
甲型流感预防哮喘的机制
- 批准号:
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- 资助金额:
$ 37.75万 - 项目类别:
Mechanisms by Which Influenza A Protects Against Asthma
甲型流感预防哮喘的机制
- 批准号:
7107940 - 财政年份:2005
- 资助金额:
$ 37.75万 - 项目类别:
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