Intestinal Mucosal Immune and Functional Response to Gastric and Enteric Pathogen

对胃肠道病原体的肠粘膜免疫和功能反应

• 批准号: 7701565
• 负责人: Alessio Fasano
• 金额: $ 29.53万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-18 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7701565
• 关键词: Adult; Affect; Animals; Antigens; Attenuated Live Virus Vaccine; Bacteria; Bathing; Biochemistry; Biological Assay; Biology; Biopsy; Biopsy Specimen; Cell Line; Cells; Clinical; Complex; Cytokine Gene; Defect; Deletion Mutation; Dendritic Cells; Development; Diagnostic; Disease; Enteral; Environment; Epithelial; Equilibrium; Esophagogastroduodenoscopy; Event; Exposure to; Gene Expression; Genetic; Genomics; Helicobacter Infections; Helicobacter pylori; Homeostasis; Human; Immune; Immune response; Infection; Inflammation; Inflammatory; Institutes; Intestinal Mucosa; Intestines; Knockout Mice; Lasers; Lead; Light; Measures; Mediating; Microbe; Microscopy; Molecular Biology; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Nutrient; Outcome; Pathway interactions; Pattern recognition receptor; Permeability; Physiological; Primates; Production; Proteomics; Research; Role; Salmonella typhi; Salmonella typhimurium; Sampling; Science; Shigella dysenteriae; Signal Transduction; Small Intestines; Solutions; Stimulus; Stomach; Symptoms; Systemic disease; TLR4 gene; Tight Junctions; Time; Tissues; Toll-like receptors; Vaccinated; Vaccines; Virulence; bacterial genetics; cell type; cytokine; design; enteric pathogen; gastrointestinal; intestinal epithelium; microbial community; microorganism; microorganism interaction; nonhuman primate; pathogen; prevent; research study; response; trafficking; trait; vaccine candidate; vaccine development; young adult

The intestinal epithelium presents the largest mucosal barrier between the internal host milieu and the external environment. Under physiological circumstances antigen trafficking occurs through three nonmutually exclusive pathways: transcellular, paracellular, and dendritic cell sampling within the intestinal lumen. When the delicate balance between controlled antigen trafficking and host immune response is lost, severe inflammation and overt clinical symptoms may develop. This negative outcome may be influenced by host genetic makeup, virulence traits of the intestinal pathogens, or the combination of both. The outcome of the interplay between host and intestinal microorganisms is influenced by the fact that the intestinal epithelium is extremely dynamic and exquisitely responsive to stimuli of innumerable variety and it is populated by a complex climax community of microbial partners, far more numerous than the cells of the intestine itself. In normal homeostasis, the gastrointestinal epithelial layer forms a tight, but selective barrier: microbes and most antigens are held at bay, but nutrients from the essential to the trivial are absorbed efficiently. Moreover, the tightness of the epithelial barrier is itself dynamic and depends on tight junctions (TJ) competency, though the mechanisms governing and affecting their permeability are poorly understood. What is becoming increasingly clear is that defects in epithelial permeability are associated with a large number of local and even systemic disorders. A common feature of enteric infections is their ability to increase epithelial permeability, an effect that initiates and promotes the host immune response. Mucosal permeability is also a factor in the delivery of mucosally introduced vaccines. With this project, we intend to capitalize on our combined expertise in mucosal biology, proteomics, genomics, microbiomics, biochemistry, and molecular biology to determine the role of alterations in mucosal barrier function in host-microbial interactions affecting antigen trafficking that lead to local and systemic immune responses to gastric and enteric pathogens. We will take full advantage of a very conducive environment that includes the Mucosal Biology Research Center, the Center for Vaccine Development and The Institute of Genomic Science, all thematically relevant to this proposal.

肠上皮是宿主内部环境和外部环境之间最大的粘膜屏障。 外部环境。在生理情况下，抗原运输通过三个非相互的过程发生 独家途径：肠道内跨细胞、旁细胞和树突状细胞采样 流明。当受控抗原运输和宿主免疫反应之间的微妙平衡失去时， 可能会出现严重的炎症和明显的临床症状。这种负面结果可能受到以下因素的影响 宿主基因组成、肠道病原体的毒力特征或两者的组合。结果 宿主和肠道微生物之间的相互作用受到肠道微生物的影响 上皮细胞极其活跃，对无数种刺激反应灵敏， 由复杂的微生物伙伴顶极群落组成，其数量远多于细胞的数量 肠本身。在正常的体内平衡中，胃肠道上皮层形成紧密但选择性的屏障： 微生物和大多数抗原都被阻止，但从必需到微不足道的营养物质都被吸收 高效。此外，上皮屏障的紧密度本身是动态的并且取决于紧密连接 （TJ）能力，尽管人们对控制和影响其渗透性的机制知之甚少。 越来越清楚的是，上皮通透性缺陷与大量的 一些局部甚至全身疾病。肠道感染的一个共同特征是它们能够 增加上皮通透性，这是一种启动和促进宿主免疫反应的作用。粘膜 渗透性也是粘膜引入疫苗递送的一个因素。通过这个项目，我们打算 利用我们在粘膜生物学、蛋白质组学、基因组学、微生物组学、生物化学、 和分子生物学来确定宿主微生物中粘膜屏障功能改变的作用 影响抗原运输的相互作用，导致对胃的局部和全身免疫反应 和肠道病原体。我们将充分利用一个非常有利的环境，包括 粘膜生物学研究中心、疫苗研制中心、基因组研究所 科学，所有主题都与该提案相关。