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Contribution of Helicobacter pylori HomA and HomB to colonization and disease

幽门螺杆菌 HomA 和 HomB 对定植和疾病的贡献

基本信息

批准号：
10434145
负责人：
ANGELA MELTON-CELSA
金额：
$ 19.06万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-21 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434145
关键词：
Address Adherence Adhesions Affect Animals Bacteria Biological Process Cells Chronic Clinical Complement Data Detection Development Disease Disease Progression Dose Duodenal Ulcer Dysplasia Elements Environment Epidemiology Epithelial Cells Etiology Exposure to Gastric ulcer Gastritis Gene Combinations Genes Genome Genomics Gerbils Helicobacter Helicobacter Infections Helicobacter pylori Helicobacter pylori associated gastric disease IL8 gene Immune Evasion Immune system In Vitro Infection Inflammation Inflammation Mediators Knock-out Location Mechanics Membrane Proteins Microbial Biofilms Modeling Molecular Mucous body substance Patient Isolators Patients Peptic Ulcer Play Population Production Protein Array Protein Family Proteins Publishing Regulation Role Series Severity of illness Signal Transduction Stomach Stomach Diseases Stress Testing Time Tissues Ulcer Virulence Virulence Factors Work cohort cytokine design environmental stressor epidemiology study global health immune clearance in vivo malignant stomach neoplasm member mutant novel novel therapeutics prevent protein B protein function public health relevance response virtual

项目摘要

Abstract: Helicobacter pylori chronically infects 50% of the world’s population and is a significant cause of gastric cancer. In the stomach, the bacterium interacts with host cells and elaborates virulence factors that directly influence disease etiology. To maintain colonization within this niche, H. pylori needs mechanisms to withstand mechanical clearance during the sloughing of epithelial cells and mucous, as well as mechanisms to prevent detection and clearance by the immune system. Genes encoding for outer membrane proteins (OMPs) constitute approximately 4% of the H. pylori genome, and it is likely that this extensive array of proteins may play a crucial role in establishing and maintaining infection by aiding in adhesion and/or immune evasion. Thus, the OMPs likely serve as key elements of the host-bacterium interface. In addition, several variable OMPs have been shown to be associated with more severe disease presentations such as gastric ulcers and gastric cancer. Included among these virulence-associated OMPs is Helicobacter Outer Membrane Protein B (HomB). HomB is highly similar to HomA and the two have been shown to have the ability to occupy two primary loci, locus A and locus B in the H. pylori genome; some strains carry both genes, while some carry one or the other. There are no studies that address the implications of the two possible genomic locations for homA and homB. Furthermore, despite the fact that in vitro studies indicate a role for HomB in adherence, virtually no other molecular studies have been conducted to assess the role of HomA and HomB during H. pylori infection. To gain a better understanding of the expression and function of these two OMPs, we propose detailed molecular studies that will directly examine expression of homA and homB in response to environmental stresses that mimic those found within the gastric environment. Furthermore, using a series of constructed isogenic mutant and complementation strains that carry all possible single gene combinations of homA and homB, we will directly assess the role of HomA and HomB in colonization and disease progression in the Mongolian gerbil model of infection. The described studies will provide novel information concerning expression and function of HomA and HomB. This information may in turn provide clues to the development of novel therapeutics that are designed to specifically target these OMPs.

摘要：幽门螺杆菌慢性感染50%的世界人口，并且是胃溃疡的重要原因。癌在胃中，细菌与宿主细胞相互作用并产生毒力因子，直接影响疾病病因。为了在这个生态位内维持殖民化，H。幽门螺杆菌需要机制，在上皮细胞和粘液脱落期间承受机械清除，以及防止免疫系统检测和清除的机制。基因编码外膜蛋白（OMPs）约占H. pylori基因组，这很可能是一系列广泛的蛋白质可能在建立和维持感染中起着至关重要的作用，粘附和/或免疫逃避。因此，外膜蛋白可能是宿主细菌的关键元件接口.此外，几种可变的外膜蛋白已被证明与更严重的疾病有关。如胃溃疡和胃癌。包括在这些药物相关OMP中是螺杆菌外膜蛋白B（HomB）。HomB与HomA高度相似，显示具有占据H中的两个主要位点，位点A和位点B的能力。幽门螺杆菌基因组;一些菌株携带两种基因，而有些菌株携带一种或另一种。目前还没有研究 homA和homB的两个可能的基因组位置的含义。此外，尽管虽然体外研究表明HomB在粘附中的作用，但实际上没有其他分子研究评估HomA和HomB在H.幽门感染更好地了解这两个外膜蛋白的表达和功能，我们提出了详细的分子研究，将直接研究homA和homB在模拟环境应激时的表达，在胃的环境中。此外，利用构建的一系列同基因突变体，携带homA和homB的所有可能的单基因组合的互补菌株，我们将直接评估HomA和HomB在蒙古沙鼠中的定植和疾病进展中的作用感染的模式。所描述的研究将提供有关表达和功能的新信息 A和B。这些信息反过来可能为开发新的治疗方法提供线索专门针对这些外膜蛋白的药物