Host and Bacterial Factors in Disease due to H. pylori

描述（由申请人提供）：H。幽门螺杆菌被称为当今世界人类最常见的传染病。在世界范围内，50-100%的人感染H。幽门螺杆菌，但只有少数发展的临床症状的疾病。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有助于疾病，但所涉及的特定细菌因素及其促进定植和诱导严重疾病表现的机制尚不清楚。本项目的总体目标是研究这些机制。在第一个资助期间，我们开发了一种严重疾病的小鼠模型，其中可以评估宿主和细菌因素对疾病严重表现的贡献。我们利用这个模型来确定T细胞亚群和细胞因子，有助于疾病，我们确定了一个细菌因子，脂多糖O-抗原，诱导有害的宿主反应，从而有助于疾病的结果，我们确定了一个H。pylori启动子，cag 15，其在体内被上调并且可能代表新的毒力因子。在本更新中，我们将研究O抗原和cagl 5在H. pylori致病机制的研究，并使用新开发的启动子陷阱来鉴定H. pylori基因在体内上调。这三个具体目标是： 具体目的1：验证cag 15在H. pylori，并确定cag 15基因产物在定殖和疾病中的作用。 具体目标2：使用ureB报告基因构建体进行启动子捕获，鉴定由体内生长诱导的新的定植因子，并检验上调基因对于H.幽门。 具体目标3：检验H.幽门螺杆菌脂多糖通过受体介导的抗原呈递细胞活化诱导胃炎。这些目标的成功完成将导致对H. pylori相关疾病的研究，并为开发新的治疗方法提供基础。

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.