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

• 批准号: 10301421
• 负责人: D. SCOTT MERRELL
• 金额: $ 22.87万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-21 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301421
• 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

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.

抽象的： 幽门螺杆菌长期感染全球 50% 的人口，是胃病的重要病因 在胃中，细菌与宿主细胞相互作用并产生直接作用的毒力因子。 为了维持在这个生态位内的定植，幽门螺杆菌需要机制来影响疾病的病因。 在上皮细胞和粘液脱落过程中承受机械间隙，以及 防止免疫系统检测和清除外源编码基因的机制。 膜蛋白 (OMP) 约占幽门螺杆菌基因组的 4%，这很可能是 广泛的蛋白质阵列可能通过帮助建立和维持感染而发挥至关重要的作用 因此，OMP 可能是宿主细菌的关键元件。 此外，一些可变的 OMP 已被证明与更严重的疾病有关。 包括胃溃疡和胃癌等与毒力相关的 OMP。 螺杆菌外膜蛋白 B (HomB) 与 HomA 高度相似，两者已被鉴定。 显示出能够占据幽门螺杆菌基因组中的两个主要基因座：基因座 A 和基因座 B； 菌株携带这两种基因，而有些菌株携带其中一种或另一种基因。目前还没有研究解决这一问题。 此外，尽管事实上，homA 和 homB 的两个可能的基因组位置的含义。 体外研究表明 HomB 在依从性方面发挥作用，但几乎没有其他分子研究表明 旨在评估 HomA 和 HomB 在幽门螺杆菌感染期间的作用，以获得更好的了解。 为了了解这两种 OMP 的表达和功能，我们提出了详细的分子研究，将直接 检查 homA 和 homB 响应环境应激的表达，模拟所发现的环境应激 此外，使用一系列构建的同基因突变体和 携带 homA 和 homB 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 在蒙古沙鼠定植和疾病进展中的作用 所描述的研究将提供有关表达和功能的新信息。 HomA 和 HomB 的信息可能反过来为新型疗法的开发提供线索。 专门针对这些 OMP 设计的。