The Role of Chemotaxis in Helicobacter pylori Distribution in the Host

趋化性在幽门螺杆菌在宿主体内分布中的作用

• 批准号: 9118193
• 负责人: Karen J Guillemin
• 金额: $ 31.69万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118193
• 关键词: Acids; Adenocarcinoma; Affinity; Anterior; Antibiotics; Antral; Bacteria; Binding; Biochemical; Biological Assay; Cells; Chemicals; Chemoreceptors; Chemotaxis; Confocal Microscopy; Cues; Data; Disease; Disease Outcome; Drug or chemical Tissue Distribution; Duodenal Ulcer; Engineering; Environment; Epithelial; Epithelial Cells; Epithelium; Gastric Glands; Gastric Parietal Cells; Gastritis; Habitats; Health; Helicobacter Infections; Helicobacter pylori; Human; Impairment; Individual; Infection; Knowledge; Lead; Ligands; Malignant Neoplasms; Measures; Mediating; Medical; Methods; Microbial Biofilms; Movement; Mucous Membrane; Mus; Organ; Pathogenesis; Pattern; Perception; Periplasmic Binding Proteins; Population; Property; Proteins; Research Personnel; Resolution; Role; Signal Transduction; Stomach; Stomach Diseases; Structure; Surface; System; Testing; Tropism; Ulcer; Urea; VAI-2; base; cell motility; density; design; in vivo Model; insight; monolayer; mutant; next generation; novel; pathogen; periplasm; prevent; quorum sensing; receptor; response; structural biology

DESCRIPTION (provided by applicant): Helicobacter pylori is a human gastric pathogen that colonizes half the world's population and causes a wide range of diseases including gastritis, ulcers, and cancer. The distribution of the bacteria in the stomach is correlated with disease outcomes, but the factors that determine this distribution are unknown. We hypothesize that chemotaxis, the ability of bacteria to sense and orient their movement in response to chemical gradients in their environment is a key determinant of H. pylori distribution in the stomach. H. pylori is ideally suited for testing the role of bacterial chemotaxis in tissue distribution, becaue it has a simple chemotaxis system with only three core chemoreceptors and it colonizes an organ with extreme chemical gradients. This proposal builds on our novel insights into the ligands and sensing mechanisms of H. pylori chemoreceptors. In this proposal, we will use structural, biophysical, and biochemical approaches to understand the precise mechanisms by which H. pylori chemoreceptors sense three key chemicals that define three important axes in the stomach environment: urea (secreted from the gastric epithelium, defining the epithelial to luminal axis), the bacterial-produced quorum sensing molecule autoinducer-2 (defining regions of high bacterial density in the gastric glands versus the overlying mucosa), and acid (produced by the parietal cells in the anterior corpus region, defining the corpus to antrum, as well as the epithelial to luminal axis in the corpus). We have engineered mutant H. pylori that are specifically defective in sensing one of these three chemicals and we have developed highly sensitive assays for quantifying H. pylori chemotactic responses. We will use these existing mutants, and others that we engineer based on our new insights into the chemosensing mechanisms, to understand how H. pylori cells organize themselves in response to chemical signals on cultured epithelial monolayers and during infection of the mouse stomach. Knowledge gained from these studies will lead to new strategies for preventing and treating H. pylori infections by altering the bacteria's distribution in the stomach. More generally, these studies will provide novel insights into how bacterial pathogens perceive and navigate the host environment, knowledge which will be crucial for designing the next generation of antibiotics that specifically target within-host properties of bacterial invaders.

描述（由申请人提供）：幽门螺杆菌是一种人类胃病原体，将世界一半的人口殖民，并引起各种疾病，包括胃炎，溃疡和癌症。细菌在胃中的分布与疾病结局相关，但是确定该分布的因素尚不清楚。我们假设趋化性，细菌对环境中化学梯度的感知和定向运动的能力是胃中幽门螺杆菌分布的关键决定因素。幽门螺杆菌非常适合测试细菌趋化性在组织分布中的作用，因为它具有一个简单的趋化性系统，只有三个核心化学感受器，并且在具有极端化学梯度的器官中定居。该提议建立在我们对幽门螺杆菌化学感受器的配体和传感机理的新见解的基础上。 In this proposal, we will use structural, biophysical, and biochemical approaches to understand the precise mechanisms by which H. pylori chemoreceptors sense three key chemicals that define three important axes in the stomach environment: urea (secreted from the gastric epithelium, defining the epithelial to luminal axis), the bacterial-produced quorum sensing molecule autoinducer-2 (defining regions of胃腺与上覆的粘膜的高细菌密度和酸（由前菌群区域的顶壁细胞产生，定义为con子，以及在con中的上皮到腔轴）。我们已经设计了幽门螺杆菌，这些突变体在感知这三种化学物质之一时特异性有缺陷，并且我们开发了高度敏感的测定法，以量化幽门螺杆菌趋化反应。我们将使用这些现有的突变体以及基于我们对化学传感机制的新见解来设计的其他突变体，以了解幽门螺杆菌细胞如何根据培养的上皮单层和小鼠胃中感染的化学信号来组织自己。从这些研究中获得的知识将导致通过改变细菌在胃中的分布来预防和治疗幽门螺杆菌感染的新策略。更普遍地，这些研究将提供有关细菌病原体如何感知和导航宿主环境的新见解，这对于设计下一代的抗生素至关重要，这些抗生素是针对细菌入侵者的主宿主特性的。