The Role of Chemotaxis in Helicobacter pylori Distribution in the Host

描述（由申请人提供）：幽门螺杆菌是一种人类胃病原体，在世界上一半的人口中定植，并引起胃炎，溃疡和癌症等多种疾病。胃中细菌的分布与疾病的结果相关，但决定这种分布的因素尚不清楚。我们假设趋化性，即细菌根据环境中的化学梯度感知和定向运动的能力，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测试细菌在组织分布中的趋化作用，因为它有一个简单的趋化系统，只有三个核心的趋化受体，它在具有极端化学梯度的器官上定植。这一建议建立在我们对幽门螺杆菌化学感受器的配体和传感机制的新见解之上。在本提案中，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胃环境中定义三个重要轴的三种关键化学物质的精确机制：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自诱导剂-2（定义胃腺与上覆粘膜的高细菌密度区域）和酸（由前体区的顶叶细胞产生，定义体到腔，以及体中的上皮到腔轴）。我们已经设计了突变型幽门螺杆菌，它在感知这三种化学物质中的一种方面有特殊缺陷，我们已经开发出高度敏感的方法来定量幽门螺杆菌的趋化反应。我们将利用这些现有的突变体，以及基于我们对化学感应机制的新见解而设计的其他突变体，来了解幽门螺杆菌细胞如何组织自己，以响应培养的上皮单层和小鼠胃感染期间的化学信号。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。更一般地说，这些研究将为细菌病原体如何感知和导航宿主环境提供新的见解，这些知识将对设计下一代抗生素至关重要，这些抗生素专门针对宿主内细菌入侵者的特性。

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.