The Role of Chemotaxis in Helicobacter pylori Distribution in the Host

描述(申请人提供)：幽门螺杆菌是一种人类胃部病原体，居住在世界上一半的人口中，导致多种疾病，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位其运动的能力，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于测试细菌趋化在组织分布中的作用，因为它有一个简单的趋化系统，只有三个核心化学受体，而且它定植于一个具有极端化学梯度的器官。这一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。在这项提议中，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受体感知三种关键化学物质的确切机制，这三种化学物质定义胃环境中三个重要的轴：尿素(从胃上皮分泌，定义上皮到管腔轴)、细菌产生的群体感应分子自动诱导器-2(定义胃腺相对于覆盖的黏膜中细菌密度高的区域)和酸(由体部前区域的壁细胞产生，定义体腔到胃窦，以及语体中的上皮到腔轴)。我们已经设计出对这三种化学物质中的一种具有特定缺陷的突变幽门螺杆菌，并开发了用于量化幽门螺杆菌趋化反应的高度敏感的分析方法。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设计的其他突变体，以了解幽门螺杆菌细胞如何对培养的上皮单层上的化学信号做出反应以及在小鼠胃感染期间如何组织自己。从这些研究中获得的知识将导致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新策略。更广泛地说，这些研究将为细菌病原体如何感知和导航宿主环境提供新的见解，这些知识将对设计专门针对细菌入侵者的宿主内特性的下一代抗生素至关重要。

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.