Pathogenesis of Helicobacter pylori infection

幽门螺杆菌是一种革兰氏阴性细菌，在人的胃中定居。幽门螺杆菌感染是 与远端胃癌症以及消化性溃疡疾病的风险增加有关。世界 卫生组织已将幽门螺杆菌列为I型致癌物质，胃癌位居第三 全球与癌症相关的死亡原因。这项工作的长期目标是理解分子 幽门螺杆菌持续定植于人胃粘膜的机制，了解 幽门螺杆菌感染导致胃癌或消化性疾病发生的分子机制 预防溃烂，并制定预防这些疾病的有效战略。要实现这些长期目标 目的：我们试图了解定位于幽门螺杆菌表面的细菌蛋白的作用。H. 幽门螺杆菌基因组包含50多个基因，被预测为编码外膜蛋白(OMP)。 已有几种OMPS被报道介导幽门螺杆菌与胃上皮细胞的黏附，但其功能 大多数幽门螺杆菌OMP尚不为人所知。这一提议的总体假设是幽门螺杆菌利用 在感染过程的不同阶段的特定OMP，以优化胃的初始定植和 在胃粘膜炎症反应存在的情况下促进持续定植，从而 促进胃病的发展。具体目标是：(I)界定两个组织的角色： 组成信号转导系统(TCS)在调节编码OMP的基因中，(Ii)定义OMPS 在促进幽门螺杆菌在胃的定植方面起主导作用，以及(Iii)定义 特定OMP促进幽门螺杆菌在胃的定植和调节发育的过程 胃病的症状。为了实现目标1，我们将比较野生型和突变株的转录本， 采用RNA-seq和定量RT-PCR方法。为了实现目标2，我们将用一个库感染小鼠 含有OMP编码蛋白突变的菌株，每个菌株都标有不同的核苷酸条形码，以及 然后将使用高通量测序来分析定植于胃的细菌种群。至 完成目标3，我们将在体内通过使用An来调节选定的OMP编码基因的表达 诱导型启动子。总而言之，这些实验将为了解特定的 OMPS在促进胃的初始定植、持久化和疾病方面的作用。

Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach. H. pylori infection is associated with an increased risk of cancer of the distal stomach, as well as peptic ulcer disease. The World Health Organization has classified H. pylori as a type I carcinogen, and gastric cancer is the third leading cause of cancer-related death worldwide. The long-term goals of this work are to understand the molecular mechanisms that allow H. pylori to persistently colonize the human gastric mucosa, to understand the molecular mechanisms by which H. pylori infection leads to the development of gastric cancer or peptic ulceration, and to develop effective strategies for the prevention of these diseases. To achieve these long-term goals, we seek to understand the actions of bacterial proteins that are localized on the surface of H. pylori. H. pylori genomes contain more than 50 genes that are predicted to encode outer membrane proteins (OMPs). Several OMPs have been reported to mediate H. pylori adherence to gastric epithelial cells, but the functions of most H. pylori OMPs are not known. The overall hypothesis of this proposal is that H. pylori utilizes specific OMPs at various stages of the infectious process to optimize initial colonization of the stomach and to facilitate persistent colonization in the presence of a gastric mucosal inflammatory response, thereby contributing to the development of gastric disease. The specific aims are (i) To define the role of two- component signal transduction systems (TCSs) in regulating genes encoding OMPs, (ii) To define OMPs that have a dominant role in promoting H. pylori colonization of the stomach, and (iii) To define temporal features of processes by which specific OMPs promote H. pylori colonization of the stomach and modulate development of gastric disease. To accomplish Aim 1, we will compare the transcriptomes of wild-type and mutant strains, using RNA-seq and quantitative RT-PCR methods. To accomplish Aim 2, we will infect mice with a library of strains containing mutations in OMP-encoding proteins, each labeled with a distinct nucleotide bar code, and then will use high throughput sequencing to analyze the bacterial populations colonizing the stomach. To accomplish Aim 3, we will regulate the expression of selected OMP-encoding genes in vivo through use of an inducible promoter. Collectively, these experiments will provide important new insights into the roles of specific OMPs in promoting initial colonization of the stomach, persistence and disease.