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: 8652710
• 负责人: Karen J Guillemin
• 金额: $ 32.24万
• 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/8652710
• 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; 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; public health relevance; quorum sensing; receptor; response; structural biology

PROJECT SUMMARY 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, because 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.

项目总结 幽门螺杆菌是一种人类胃部病原体，占世界人口的一半，并引起广泛的 一系列疾病，包括胃炎、溃疡和癌症。细菌在胃中的分布是 与疾病结果相关，但决定这种分布的因素尚不清楚。我们假设 这种趋化性，即细菌感知和定位自己的运动以响应化学梯度的能力 他们所处的环境是幽门螺杆菌在胃中分布的关键决定因素。幽门螺杆菌非常适合于 测试细菌趋化性在组织分布中的作用，因为它有一个简单的趋化性系统， 只有三个核心化学感受器，它定植在一个具有极端化学梯度的器官上。这项建议 建立在我们对幽门螺杆菌化学受体的配体和传感机制的新见解的基础上。在这 提案，我们将使用结构、生物物理和生化方法来了解 幽门螺杆菌化学感受器感知三种关键化学物质的机制 胃环境：尿素(由胃上皮分泌，定义上皮到管腔轴)， 细菌产生的群体感应分子自动诱导剂-2(定义细菌密度高的区域 胃腺与上覆粘膜)和酸(由前体壁细胞产生) 区域，定义体部至胃窦，以及体部的上皮轴至管腔轴)。我们有 幽门螺杆菌的工程突变株在感知这三种化学物质中的一种方面存在明显缺陷，而我们 已经开发出高度灵敏的方法来量化幽门螺杆菌的趋化反应。我们将使用这些 现有的突变体，以及我们基于对化学传感机制的新见解而设计的其他突变体， 了解幽门螺杆菌细胞如何在培养的上皮细胞上对化学信号作出反应 在小鼠胃单分子层和感染期间。从这些研究中获得的知识将导致新的 通过改变幽门螺杆菌在胃中的分布来预防和治疗幽门螺杆菌感染的策略。 更广泛地说，这些研究将为细菌病原体如何感知和导航提供新的见解 宿主环境，对设计下一代抗生素至关重要的知识， 特别针对细菌入侵者的宿主内特性。