The Role of Chemotaxis in Helicobacter pylori Distribution in the Host

项目摘要 幽门螺杆菌是一种人类胃病原体，占世界人口的一半， 一系列疾病，包括胃炎、溃疡和癌症。胃中细菌的分布是 与疾病结局相关，但决定这种分布的因素尚不清楚。我们假设 趋化性，即细菌感知和定位其运动以响应化学梯度的能力， 它们的环境，是H的关键决定因素。幽门螺杆菌在胃中的分布。H.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，因为它有一个简单的趋化系统， 只有三个核心化学感受器，它以极端的化学梯度定殖器官。这项建议 建立在我们对H的配体和传感机制的新见解的基础上。幽门化学感受器在这 建议，我们将使用结构，生物物理和生物化学的方法来了解精确的 H.幽门化学感受器感知三种关键化学物质，它们定义了幽门螺杆菌的三个重要轴， 胃环境：尿素（从胃上皮分泌，定义上皮到腔轴）， 细菌产生的群体感应分子autoinducer-2（定义了高细菌密度的区域， 胃腺与上覆粘膜）和酸（由前体中的壁细胞产生 区域，限定了体到窦，以及体中的上皮到腔轴）。我们有 工程突变体H.幽门螺杆菌在感知这三种化学物质中的一种时有特异性缺陷， 已经开发了高灵敏度的测定H.幽门趋化反应。我们将会用这些 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H.幽门螺杆菌细胞对培养的上皮细胞上的化学信号作出反应， 单层和在小鼠胃感染期间。从这些研究中获得的知识将导致新的 预防和治疗H.通过改变细菌在胃中的分布来预防幽门螺杆菌感染。 更一般地说，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，这对于设计下一代抗生素至关重要， 特异性针对细菌入侵者的宿主内特性。

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.