Human airway microfold cells in mucosal immunity to bacterial pathogens

人气道微褶皱细胞对细菌病原体的粘膜免疫

• 批准号: 9170079
• 负责人: MICHAEL SHILOH
• 金额: $ 45.64万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-21 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9170079
• 关键词: Accounting; Adenoidal structure; Aerosols; Animals; Antibodies; Antigen Presentation; Antigens; Apical; Applied Genetics; B-Lymphocytes; Bacillus anthracis; Bacteria; Binding; Biochemical; Biochemical Genetics; Biology; Breathing; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Surface Receptors; Cell physiology; Cells; Cessation of life; Data; Dendritic Cells; Development; Disease; Endocytosis; Genus Mycobacterium; Host Defense; Human; Immune response; Immune system; Immunity; Immunologics; Infection; Invaded; Lymphoid Tissue; M cell; Measures; Mediating; Modeling; Molecular; Mucosal Immunity; Mucous Membrane; Mus; Mycobacterium tuberculosis; Nasopharynx; Natural Immunity; Nose; Oral; Oral mucous membrane structure; Organism; Oropharyngeal; Pneumonia; Population; Process; Research; Respiratory Mucosa; Role; Site; Specialized Epithelial Cell; Staphylococcus aureus; Streptococcus pneumoniae; System; Systemic disease; T cell response; T-Lymphocyte; Testing; Tonsil; Trees; Tuberculosis; Virulence Factors; Work; abstracting; adaptive immunity; base; genetic approach; human tissue; immune activation; improved; in vivo; innate immune function; innovation; lymph nodes; macrophage; microbicide; migration; mortality; mycobacterial; novel; pathogen; prevent; receptor; respiratory; response; tool; transcytosis

Project Summary/Abstract The nasopharyngeal and respiratory mucosa represents a primary barrier to infection by inhaled organisms. However, many pathogens have adapted and can disseminate beyond the oral and respiratory mucosa to cause systemic disease. Such pathogens include Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus pneumonia, and Bacillus anthracis. Together these pathogens account for millions of deaths worldwide every year, and in particular, M. tuberculosis continues to be a devastating global pathogen, alone causing two million deaths annually and latently infecting a third of the world’s population. Lining the respiratory mucosa are specialized epithelial cells that function to transcytose mucosal antigens from the apical, mucosal lumen to the basolateral space. These cells, known as microfold or M-cells, overlie mucosal associated lymphatic tissue where macrophages and dendritic cells await to ingest and present antigens to B-cells and T- cells. We hypothesized that M. tuberculosis has evolved to penetrate the mucosa via M-cells, and our preliminary data indicate that M. tuberculosis indeed utilizes M-cells to initiate disease. Blocking M-cell development or secretion of an M. tuberculosis virulence factor prevents lymph node dissemination and mortality from M. tuberculosis infection in mice. We will apply genetic, biochemical, immunologic and animal approaches to determine the functional role of M-cells in mucosal and systemic immunity against respiratory pathogens. Thus, in the proposed research we will (1) Characterize the transcytosis machinery leveraged by bacteria to cross airway M-cells, (2) Assess the role of airway M-cells in inducing innate and adaptive immunity in mice and (3) Determine the role of airway M-cells in the immune response using primary human tissues. The proposed work is expected to identify how M-cells bind and transcytose M. tuberculosis and similar bacteria, and the consequences of M-cell mediated transcytosis to innate and adaptive immune responses.

项目概要/摘要 鼻咽和呼吸道粘膜是抵抗吸入生物体感染的主要屏障。 然而，许多病原体已经适应并可以传播到口腔和呼吸道粘膜之外 引起全身性疾病的病原体包括结核分枝杆菌、金黄色葡萄球菌、 肺炎链球菌和炭疽杆菌共同导致数百万人死亡。 每年在世界范围内发生，特别是结核分枝杆菌仍然是一种毁灭性的全球病原体 每年造成 200 万人死亡，潜伏感染世界三分之一的人口。 粘膜是专门的上皮细胞，其功能是转胞吞来自顶端、粘膜的粘膜抗原。 这些细胞被称为微褶皱或 M 细胞，覆盖粘膜相关空间。 淋巴组织，巨噬细胞和树突状细胞等待吞噬抗原并将其呈递给 B 细胞和 T 细胞 我们探索了结核分枝杆菌已经进化为通过 M 细胞穿透粘膜，并且我们的研究 初步数据表明，结核分枝杆菌确实利用 M 细胞来阻断 M 细胞引发疾病。 结核分枝杆菌毒力因子的产生或分泌可防止淋巴结传播和 小鼠结核分枝杆菌感染的死亡率我们将应用遗传、生化、免疫学和动物学方法。 确定 M 细胞在呼吸道粘膜和全身免疫中功能作用的方法 因此，在拟议的研究中，我们将（1）表征转胞吞机制。 细菌穿过气道 M 细胞，(2) 评估气道 M 细胞在诱导先天性和适应性免疫中的作用 (3) 使用原代人体组织确定气道 M 细胞在免疫反应中的作用。 拟议的工作预计将确定 M 细胞如何结合和转胞吞结核分枝杆菌和类似细菌， 以及 M 细胞介导的转胞吞作用对先天性和适应性免疫反应的影响。