MODELING AIRWAY RESPONSE TO BORDETELLA SP INFECTION

描述(申请人摘要)：虽然最近才开始接种疫苗 20世纪40年代一直有效地降低了波尔德氏菌病的发病率 在人类中，这种疾病仍然是地方病，影响着6000多万人 每年一次。在美国，波尔德氏菌病的报告发病率为 低，每年有2,000-6,000例确诊病例。但是，这个数字是一个 由于诊断困难而被低估，而波尔德氏菌病 自那以来，免疫缺陷人群和成年人群的数量一直在稳步增长 20世纪70年代末。本研究旨在了解波尔德氏菌 衍生因子及其对心力衰竭的发生和发展的影响 呼吸道细胞发病机制。细菌病原体与其相互作用的研究进展 宿主的范围可以从建立共生关系到 潜在的致命性疾病。在发病过程中，细菌不断地监测 并相应地调节毒力基因的表达。它是 认为病原菌为波尔德氏菌。表达特定的基因产物，以允许 用于优先结合呼吸道上皮中的纤毛细胞。 此外，有人认为这种结合启动了宿主细胞的信号转导 途径--包括细胞内钙离子浓度的瞬时变化 ([Ca2+]i)-和宿主细胞细胞骨架重排，有助于建立 有利于波尔德氏菌建立和发展的当地环境 SP.感染。在本方案中，原代培养的兔气管上皮 细胞和支气管败血杆菌菌株基因锁定于特定毒力 状态或表达选择性毒力基因将被用来建立细胞模型 引发波尔德氏菌的致病机制。感染。视频显微镜将是 用于分析物理附着的变化，数字成像显微镜 用免疫细胞化学检测宿主细胞的变化 与特定基因产物相关的宿主细胞细胞骨架 波尔德氏菌在细胞发病过程中。更好地理解 细菌/宿主相互作用及其生理意义 应导致更好地发展预防、治疗和治疗 防止细菌入侵的策略。

DESCRIPTION (Applicant's Abstract): Although vaccination introduced in the late 1940s has been effective in reducing the incidence of Bordetella disease in humans, the disease is still endemic, and affects more than 60 million people annually. In the United States, the reported incidence of Bordetella disease is low, with 2,000 - 6,000 diagnosed cases each year. However, this number is an underestimate due to the difficulty of diagnosis, and Bordetella disease has been steadily increasing in immunocompromised and adult populations since the late 1970s. This research is directed at the understanding of Bordetella derived factors and their impact on the initiation and the progression of airway cell pathogenesis. The interaction between bacterial pathogens and their hosts can range from the establishment of a commensal relationship to a potentially lethal disease. During pathogenesis, bacteria continually monitor their environment and adjust virulence gene expression accordingly. It is thought pathogens from Bordetella sp. express specific gene products that allow for preferential binding of ciliated cells in the airway epithelium. Furthermore, it is suggested that this binding initiates host cell signaling pathways-including transient changes in intracellular Ca2+ concentration ([Ca2+]i)-and host cell cytoskeleton rearrangements that help establish a favorable local environment for the establishment and progression of Bordetella sp. infection. In this proposal, primary cultured rabbit tracheal epithelial cells and B. bronchiseptica strains genetically locked in specific virulence states or expressing selective virulence genes will be used to model cell pathogenesis in initiating Bordetella sp. infection. Video microscopy will be used to assay changes in physical attachment, digital imaging microscopy to assay changes in host cell signaling an immunocytochemistry to assay changes in the host cell cytoskeleton associated with specific gene products produced by Bordetella sp. during cell pathogenesis. A greater understanding of bacterial/host interactions and their resulting physiological significance should lead to better development of prevention therapies and treatment strategies against bacterial invasion.