Polymicrobial induction of epithelial inflammation

描述（由申请人提供）：上皮细胞通过感知细菌产物和将中性粒细胞募集到粘膜表面，充当先天免疫系统最近的手臂。在定植过程中，这些细胞同时暴露于大量微生物产物中，目前尚不清楚这些组合如何改变上皮细胞的反应。这里提出的初步数据描述了一种在多微生物刺激环境下产生炎症的新系统。同时暴露于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，诱导上皮细胞协同产生促炎细胞因子。这种作用在体外和体内都发生，并与中性粒细胞募集有关。本建议旨在描述这种反应的机制。第一个具体目标将解决来自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和充分的假设。第二个特定目的是研究参与这一途径的特定宿主分子机制。这些研究有可能进一步了解目前对定植粘膜表面免疫反应的理解，对定植和侵袭性疾病都有影响。

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.