Host and Bacterial Factors in Disease due to H. pylori

幽门螺杆菌疾病的宿主和细菌因素

• 批准号: 7231007
• 负责人: KATHRYN A. EATON
• 金额: $ 26.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231007
• 关键词: Host; Bacterial; Factors; Disease; due

DESCRIPTION (provided by applicant): H. pylori has been called the most common infectious disease of humans in the world today. Worldwide, between 50-100% of people are infected with H. pylori, but only a minority of those develop clinical signs of disease. Almost 2 decades of research have resulted in a general consensus that both host and bacterial factors contribute to disease, but the specific bacterial factors involved and the mechanisms whereby they promote colonization and induce severe manifestations of disease are not well understood. The overall goal of this project is to investigate these mechanisms. In the first funding interval we developed a mouse model of severe disease in which the contributions of host and bacterial factors to severe manifestations of disease can be evaluated. We utilized this model to determine the T cell subsets and cytokines that contribute to disease, we identified one bacterial factor, lipopolysaccharide O-antigen, that induces a deleterious host response and thus contributes to the outcome of disease, and we identified an H. pylori promoter, cagl5, that is upregulated in vivo and likely represents a new virulence factor. In this renewal, we will investigate the roles of O-antigen and cagl 5 in H. pylori pathogenesis, and use a newly-developed promoter trap to identify H. pylori genes that are upregulated in vivo. The 3 specific aims are: Specific aim 1: To test the hypothesis that cag15 has a role in survival of H. pylori in vivo, and to determine the role of the cagl5 gene product in colonization and disease. Specific aim 2: To use a ureB reporter construct for promoter trapping, to identify novel colonization factors that are induced by growth in vivo, and to test the hypothesis that upregulated genes are essential for or facilitate colonization by and/or gastritis due to H. pylori. Specific aim 3: To test the hypothesis that the polysaccharide moiety of H. pylori lipopolysaccharide induces gastritis by receptor-mediated activation of antigen presenting cells. Successful completion of these aims will lead to improved understanding of the pathogenesis of H. pylori associated disease and provide a foundation for development of novel therapies.

描述(申请人提供)：幽门螺杆菌被称为当今世界上人类最常见的传染病。在世界范围内，50%-100%的人感染了幽门螺杆菌，但只有一小部分人出现了临床症状。近20年的研究已经达成了一个普遍的共识，即宿主和细菌因素都是疾病的致病因素，但所涉及的特定细菌因素及其促进定植和诱导疾病严重表现的机制尚不清楚。这个项目的总体目标是研究这些机制。在第一个资助期间，我们开发了一个严重疾病的小鼠模型，在该模型中，可以评估宿主和细菌因素对严重疾病表现的贡献。我们利用这个模型来确定与疾病有关的T细胞亚群和细胞因子，我们发现了一种细菌因子，脂多糖O抗原，它可以诱导有害的宿主反应，从而导致疾病的结局，我们还发现了幽门螺杆菌的启动子cagl5，它在体内上调，可能代表了一种新的毒力因子。在这次更新中，我们将研究O-抗原和cagl 5在幽门螺杆菌致病中的作用，并使用新开发的启动子陷阱来识别在体内上调的幽门螺杆菌基因。三个具体目标是： 具体目的1：验证cag15在幽门螺杆菌体内存活的假设，并确定cag15基因产物在定植和疾病中的作用。 具体目的2：使用ureB报告基因捕获启动子，鉴定由体内生长诱导的新的定植因子，并验证上调的基因在幽门螺杆菌引起的胃炎和/或胃炎的定植中所必需或促进的假说。 特异性目的3：验证幽门螺杆菌脂多糖部分通过受体介导的抗原提呈细胞活化而引起胃炎的假说。这些目标的成功实现将有助于更好地理解幽门螺杆菌相关性疾病的发病机制，并为开发新的治疗方法奠定基础。