Mathematical Models of H. Pylori gastric colonization

细菌具有高度的多样性，并已发展出多样化的机制，使其能够在一个充满活力的世界中生存。与宿主范围更广的细菌或自由生活的细菌相比，作为特定宿主的专职定居者的细菌有额外的好处和挑战。幽门螺杆菌是一种革兰氏阴性细菌，在人的胃中定居。幽门螺杆菌一旦获得，基本上会在宿主中存活(在没有抗菌治疗的情况下)，与人的胃组织密切相关，包括将幽门螺杆菌的成分注射到上皮细胞中，当存在时，是人胃中唯一的优势微生物。除了其重要的医学意义外，幽门螺杆菌还是一个模型系统，用于了解微生物在宿主中的持久性和启动机制。我们的假设是，幽门螺杆菌进化出了特定的遗传机制，以创造和控制变异，从而最大限度地保持其在胃壁龛中的持久性。我们将通过几个具体的目标来解决这一假设：在目标1中，我们将评估Hp如何使用DNA修复和重组基因控制涉及短序列重复(SSR)的基因组内变异。我们计划在体外的稳态和波动环境下研究这个问题，并使用数学模型来理解动力学的基本原理。在目标2中，我们将评估幽门螺杆菌如何控制对转化DNA的敏感性，然后在小鼠模型中确定其在体内的成本和好处。最后，在目标3中，我们计划进行实验，以了解幽门螺杆菌定植的空间定位(生物地理学)；确定在固定或振荡条件下，胃环境中幽门螺杆菌菌株的区段是否存在异质性。对于要进行的每一项实验，我们将进行数学分析，以找出微生物种群多样化和被选择的一般特性。通过这样的分析，我们希望为更深入地了解微生物如何能够在人类宿主体内长期存活奠定基础。

Bacteria are highly varied, and have developed mechanisms to diversify to enable survival in a dynamic world. Bacteria that are obligate colonizers of specific hosts have additional benefits and challenges compared with those with broader host ranges or those that are free-living. Helicobacter pylori is a gram negative bacterium that colonizes the human stomach. Once acquired, H. pylori persists in its host essentially for life (in the absence of antimicrobial therapy), is intimately related to human gastric tissues, including injection of H pylori constituents into epithelial cells, and when present, is the single dominant microbe in the human stomach. In addition to its major medical importance, H. pylori also is a model system for understanding microbial persistence in a host and the enabling mechanisms. Our hypothesis is that H. pylori evolved specific genetic mechanisms to create and control variation that maximizes its persistence in the gastric niche. We will address this hypothesis, through several Specific Aims: In Aim 1, we will assess how H. pylori controls intragenomic variation involving short sequence repeats (SSRs), using DNA repair and recombination genes. We plan to examine this question under steady state and fluctuating environments in vitro, and employ mathematical models to understand the underlying principles of the dynamics. In Aim 2, we will assess how H. pylori controls susceptibility to transforming DNA, and then determine its costs and benefits in vivo, in a murine model. Finally, in Aim 3, we plan to conduct experiments to understand the spatial localization (biogeography) of H. pylori colonization; to determine whether there is heterogeneity of sectoring of H. pylori strains in the gastric environment, under fixed or oscillating conditions. For each of the experiments to be performed, we will develop mathematical analyses to find the general properties under which the microbial populations diversify and are selected. Through such analyses, we hope to create the basis for a deeper understanding of how microbes are able to persist for long periods in their human hosts.