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（由申请人提供）：幽门螺杆菌被称为当今世界上最常见的人类传染病。在全球范围内，有50-100％的人感染了幽门螺杆菌，但只有少数人出现疾病的临床迹象。将近20年的研究导致人们普遍的共识，即宿主和细菌因素都会导致疾病，但是涉及的特定细菌因素以及它们促进定殖并引起疾病的严重表现的机制尚不清楚。该项目的总体目标是研究这些机制。在第一个资金间隔中，我们开发了一种严重疾病的小鼠模型，其中宿主和细菌因素对严重表现的疾病表现的贡献可以得到评估。我们利用该模型来确定对疾病有助于疾病的T细胞子群和细胞因子，我们确定了一种细菌因子，脂多糖o-antigen，可诱导有害的宿主反应，从而促进疾病的结果，并确定了H.幽门螺杆菌的促进剂，CAGL5，CAGL5在Vivo中是一种新的代表。在这种续签中，我们将研究O-抗原和Cagl 5在幽门螺杆菌发病机理中的作用，并使用新发达的启动子陷阱来鉴定体内上调的幽门螺杆菌基因。 3个具体目标是： 具体目的1：检验CAG15在体内幽门螺杆菌在生存中起作用的假设，并确定CAGL5基因产物在定植和疾病中的作用。 具体目的2：使用UREB报告基因构建体进行启动子捕获，以鉴定由体内生长诱导的新型定植因子，并检验以下假设：上调基因对于幽门螺杆菌而言，对通过H. 具体目的3：检验以下假设：幽门螺杆菌脂多糖的多糖部分通过受体介导的抗原呈递细胞的激活诱导胃炎。这些目标的成功完成将导致人们对幽门螺杆菌相关疾病的发病机理的了解，并为开发新疗法提供了基础。