Mathematical Models of H. Pylori gastric colonization

细菌是高度多样化的，并且已经发展出多样化的机制，以使其能够在动态世界中生存。与那些具有更广泛宿主范围或自由生活的细菌相比，作为特定宿主的专性定殖者的细菌具有额外的益处和挑战。幽门螺杆菌是一种革兰氏阴性细菌，定植在人类胃中。一旦获得，H.幽门螺杆菌在其宿主中基本上终生存在（在没有抗微生物治疗的情况下），与人胃组织密切相关，包括将幽门螺杆菌成分注射到上皮细胞中，并且当存在时，是人胃中的单一优势微生物。除了其重要的医学意义，H。幽门螺杆菌也是了解宿主中微生物持久性和启动机制的模型系统。我们假设H.幽门螺杆菌进化出特定的遗传机制，以创造和控制变异，使其在胃生态位中的持久性最大化。我们将通过几个具体目标来解决这个假设：在目标1中，我们将评估H。pylori利用DNA修复和重组基因控制基因组内变异，包括短序列重复序列（SSR）。我们计划在体外稳态和波动环境下研究这个问题，并采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H。pylori控制对转化DNA的敏感性，然后在小鼠模型中确定其体内成本和收益。最后，在目标3中，我们计划进行实验以了解H的空间定位（空间定位）。pylori定植;以确定是否有异质性的扇形H。幽门螺杆菌菌株在胃环境中，在固定或振荡条件下。对于每个要进行的实验，我们将开发数学分析，以找到微生物种群多样化和选择的一般属性。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中长期存在奠定基础。

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.