Helicobacter pylori: Tactic Responses and Persistence in the Gastric Mucosa

幽门螺杆菌：胃粘膜中的策略反应和持久性

• 批准号: 7264446
• 负责人: PAUL Stokes HOFFMAN
• 金额: $ 30.64万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264446
• 关键词: Acidity; Acids; Address; Affect; Agar; Amino Acids; Bacteria; Behavior; Bile Acids; Biological; Biological Assay; Biological Models; Blood capillaries; Campylobacter jejuni; Chemoreceptors; Chemotaxis; Classification; Count; Cytoplasm; Development; Electron Microscopy; Epithelial Cells; Epithelium; Evolution; Fluorescent Dyes; Gastric mucosa; Gastric ulcer; Gastritis; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Helicobacter; Helicobacter hepaticus; Helicobacter pylori; Histidine; Human; Hydrochloric Acid; Immunoblotting; Infection; Interleukin-12; Intestines; Knowledge; Lead; Life; Ligand Binding; Link; Maintenance; Malignant Neoplasms; Microbe; Molecular; Monitor; Mucous body substance; Mus; Orthologous Gene; Pathogenesis; Physiologic pulse; Population; Process; Proteome; Proton-Motive Force; Pulse taking; Pylorus; Radiolabeled; Range; Relative (related person); Research; Research Personnel; Role; Scanning; Score; Screening procedure; Signal Transduction; Site; Site-Directed Mutagenesis; Southern Blotting; Stomach; System; Testing; Thick; Tube; Urea; Urease; Vaccines; Video Microscopy; acid stress; base; biological adaptation to stress; blind; capillary; cell motility; deletion analysis; insight; malignant stomach neoplasm; microbial; mucosa-associated lymphoid tissue lymphoma; mutant; novel; novel therapeutics; pathogen; periplasm; programs; promoter; protonation; radiotracer; receptor; response; trait; vector

DESCRIPTION (provided by applicant): Mucosal pathogens of the gastrointestinal tract must penetrate layers of mucus in order to establish infection of the underlying mucosal epithelium. The fundamental biological question our research addresses is whether mucosal colonization is by random chance or a function of genetic traits that direct the process. We are using the human gastric pathogen Helicobacter pylori as a model system to study mucosal colonization. We hypothesize that H. pylori responds rapidly to changes in local acidity in gastric mucus, through motility-linked chemoreceptors, that monitor temporal changes in gastric acidity; and (ii) that acid pH taxis is essential for primary colonization and for persistence by enabling bacteria to escape extreme acid stress. To test this hypothesis we have developed several pH taxis assays in which H. pylori displays negative chemotactic responses to acids (not to bases) and in these assays non-gastric species H. hepaticus and Campylobacter jejuni are not pH tactic. We determined that novel chemoreceptor TIpB is required for both pH taxis and for gastric colonization. We propose the following specific aims to further test the pH taxis hypothesis: (Aim I) To isolate TIpB function by deletion of the three other chemoreceptor genes to validate TIpB function, determine acid thresholds and the relative abundance of TIpB and other Tips and by screening gastric and non-gastric species of Helicobacter to determine whether TIpB and acid sensing are unique to gastric species; (Aim II) TIpB contains unique periplasmic and HAMP domains that might participate in acid sensing and both deletion and site directed mutagenesis scanning will be used to identify which domains sense acid (periplasmic or cytoplasmic) and whether protonation of key histidine or other amino acids is required for signal transduction; (Aim III) We propose to determine how the urease system (pH stasis) and global response regulators ArsRS and HP1043 (acid stress) interface with rapid acid pH tactic behavior in directing acid survival, gastric colonization and life long persistence. Relevance: It is remarkable that H. pylori can survive and display acid pH taxis in 100 mM hydrochloric acid, a feat unmatched by any microbial pathogen studied to date. Understanding the fundamental mechanisms associated with acid survival and gastric colonization underpins all eradicative strategies from vaccines to novel therapeutics against a pathogen that infects half of the world's population.

描述（由申请人提供）：胃肠道的粘膜病原体必须穿透粘液的层，以建立基础粘膜上皮的感染。我们的研究解决的基本生物学问题是，粘膜定殖是通过随机的机会还是指导该过程的遗传特征的函数。我们使用人类胃病原体幽门螺杆菌作为研究粘膜定殖的模型系统。我们假设幽门螺杆菌通过运动性化学感受器对胃粘液的局部酸度的变化迅速反应，从而监测胃酸性的时间变化。 （ii）酸性pH出租车对于原发性定殖和持久性至关重要，使细菌能够逃脱极端的酸应激。为了检验这一假设，我们开发了几种pH出租车测定法，其中幽门螺杆菌对酸（不是碱）表现出负趋化性反应，而在这些测定中，非胃种物种H.肝杆菌和弯曲杆菌的空肠不是pH战术。我们确定pH出租车和胃定植都需要新型的化学感受器尖端。我们提出以下具体旨在进一步检验pH出租车假设的特定目的：（目标i）通过删除其他三个化学感受器基因来隔离TIPB功能，以验证TIPB功能，确定酸性阈值以及TIPB和其他尖端的相对丰度，以及其他tip和其他筛查的胃杆菌和非螺旋杆菌种类，以确定tipb和cid Acid actic Acid Sentertic semptic semant gastric semant gastric os gastric as gastric as as as ans Gastric sy gastic sy gastic sy gastic sy as as as as ans Gastric sy gastric as as ans Gastric sy ans Gastric; （AIM II）TIPB包含可能参与酸感应的独特周围和HAMP结构域，并且将使用删除和位置的定向诱变扫描来识别哪些结构域感应酸（周质或细胞质），以及质质蛋白或其他氨基酸是否需要信号转移的质子酸或其他氨基酸； （AIM III）我们建议确定尿素酶系统（pH停滞）和全球响应调节剂ARSRS和HP1043（酸应激）界面如何在指导酸生存，胃定殖和寿命长期持久性方面具有快速酸pH战术行为。相关性：值得注意的是，幽门螺杆菌可以在100 mM盐酸中生存并显示酸性pH出租车，这是迄今为止研究的任何微生物病原体所无法比拟的征服。了解与酸生存和胃定植相关的基本机制是从疫苗到新型治疗剂的所有根除策略，反对感染世界一半人群的病原体。