Polymicrobial induction of epithelial inflammation

多种微生物诱导上皮炎症

• 批准号: 7333540
• 负责人: Adam Jonathan Ratner
• 金额: $ 9.66万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7333540
• 关键词: Haemophilus influenzae; Streptococcus infection; Streptococcus pneumoniae; bacteria infection mechanism; bacterial cytopathogenic effect; bacterial toxins; biological signal transduction; cell line; cell migration; cytokine; cytoplasmic receptors; enzyme linked immunosorbent assay; host organism interaction; human tissue; inflammation; microorganism immunology; mucosal immunity; neutrophil; peptidoglycan; pore forming protein; respiratory epithelium; respiratory infections

DESCRIPTION (provided by applicant): Epithelial cells act as the most proximal arm of the innate immune system by sensing bacterial products and recruiting neutrophils to mucosal surfaces. During colonization, these cells are concurrently exposed to a vast array of microbial products, and it is not well understood how these combinations may alter the responses of epithelial cells. Preliminary data presented here describe a novel system for the generation of inflammation in the setting of polymicrobial stimulation. Concurrent exposure to two important human respiratory pathogens, S. pneumoniae and H. influenzae, induces synergistic production of proinflammatory cytokines by epithelial cells. This effect occurs both in vitro and in vivo and is associated with neutrophil recruitment. This proposal is designed to characterize the mechanism of this response. The first specific aim will address the hypothesis that specific bacterial components from S. pneumoniae and H. influenzae are necessary and sufficient for synergistic induction of inflammation. The second specific aim addresses specific host molecular mechanisms involved in this pathway. These studies have the potential to further the current understanding of immune responses at colonized mucosal surfaces, with implications for both colonization and invasive disease. This application describes a program designed to provide Dr. Adam Ratner with the skills necessary to become an independent investigator in microbial pathogenesis. Dr. Ratner has completed fellowship training in pediatric infectious diseases and will be mentored by Dr. Jeffrey Weiser, an expert in the pathogenesis of respiratory diseases. The program includes didactic study in the areas of genetics, immunology, and bacterial pathogenesis. In addition, an in-depth laboratory experience will expose Dr. Ratner to a wide variety of techniques in the areas of cell biology, biochemistry, physiology, and molecular biology, thus providing a solid foundation for beginning an independent research career.

描述(申请人提供)：上皮细胞作为先天免疫系统最近端的手臂，通过感知细菌产物并将中性粒细胞招募到粘膜表面而发挥作用。在定植过程中，这些细胞同时接触到大量的微生物产品，这些组合如何改变上皮细胞的反应尚不清楚。这里提供的初步数据描述了一种新的系统，用于在多菌刺激的背景下产生炎症。同时接触两种重要的人类呼吸道病原体肺炎链球菌和流感嗜血杆菌，可诱导上皮细胞协同产生促炎细胞因子。这一效应在体外和体内均可发生，并与中性粒细胞募集有关。这项提议旨在描述这一反应的机制。第一个具体目标将解决这样的假设，即肺炎链球菌和流感嗜血杆菌的特定细菌成分对于协同诱导炎症是必要的和充分的。第二个特定目的是解决参与这一途径的特定宿主分子机制。这些研究有可能促进目前对定植的粘膜表面的免疫反应的理解，对定植和侵袭性疾病都有意义。 本申请描述了一个计划，旨在为亚当·拉特纳博士提供必要的技能，使其成为微生物发病机制的独立研究者。拉特纳博士已经完成了儿科传染病方面的奖学金培训，并将接受呼吸系统疾病发病机制专家杰弗里·韦瑟博士的指导。该计划包括在遗传学、免疫学和细菌致病学领域的教学研究。此外，深入的实验室经验将使Ratner博士接触到细胞生物学、生物化学、生理学和分子生物学领域的各种技术，从而为开始独立的研究生涯奠定坚实的基础。