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，以便在一个动态的世界中生存。与寄主范围更广或自由生活的细菌相比，专为特定寄主定殖的细菌有额外的好处和挑战。幽门螺杆菌是一种寄居在人类胃部的革兰氏阴性细菌。一旦获得，幽门螺杆菌基本上在其宿主体内终生存在（在没有抗菌治疗的情况下），与人类胃组织密切相关，包括将幽门螺杆菌成分注射到上皮细胞中，当存在时，是人类胃中唯一的优势微生物。除了具有重要的医学意义外，幽门螺杆菌也是了解微生物在宿主中的持久性及其使能机制的模型系统。我们的假设是幽门螺旋杆菌进化出了特定的遗传机制来创造和控制变异，从而最大限度地提高了其在胃生态位中的持久性。我们将通过几个具体目标来解决这一假设：在目标1中，我们将评估幽门螺杆菌如何利用DNA修复和重组基因控制涉及短序列重复（SSRs）的基因组内变异。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，我们将评估幽门螺杆菌如何控制对转化DNA的易感性，然后在小鼠模型中确定其在体内的成本和收益。最后，在Aim 3中，我们计划通过实验来了解幽门螺杆菌定殖的空间定位（生物地理学）；确定胃环境中幽门螺杆菌菌株在固定或振荡条件下的分型是否存在异质性。对于要进行的每个实验，我们将进行数学分析，以找到微生物种群多样化和选择的一般特性。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.