Role of type 1 fimbrial mutations in the pathogenesis of pandemic E. coli

摘要 粘连是尿路感染和肠道感染发病的基本特征 大肠杆菌和甘露糖特异性1型菌毛(T1F)的定植是最关键的黏附因素。我们的 目的是了解大流行性尿路病原性克隆组T1F中的一些独特特征， ST131-H30，适应该亚克隆的尿毒力和肠道适应性。我们将专注于 菌毛甘露糖结合粘附亚单位FimH的结构-功能分析 ST131-H30特异的菌毛表达调控机制。我们将在伟大的 通过比较菌毛粘附素FimH调节黏附的能力，详细说明其功能特性 在不同的流动和抑制条件下。我们还将确定基因的功能意义 插入失活T1F、FIMB正调控基因。我们将尝试 了解这种突变如何影响T1F本身以及其他基因的表达 基因组和大肠杆菌的毒力和定植特性。最后，我们将利用动物研究来 确定ST131-H30中T1F及其变异体的适应性意义。

ABSTRACT Adhesion is an essential trait for the pathogenesis of urinary tract infections and intestinal colonization by E. coli and mannose-specific type 1 fimbriae (T1F) is the most critical adhesive factor. Our goal is to understand how some of the unique features in T1F of the pandemic uropathogenic clonal group, ST131-H30, are adaptive for this sub-clone's urovirulence and intestinal fitness. We will concentrate on the structure-functional analysis of the mannose-binding adhesive subunit of the fimbriae, FimH, and the regulatory mechanism of fimbrial expression that are specific to ST131-H30. We will characterize in great detail the functional properties of the fimbrial adhesin, FimH, by comparing its ability to mediate adhesion under various flow and inhibitory conditions. We also will determine the functional significance of genetic insertion that inactivated the gene coding for positive regulator of T1F, FimB. We will attempt to understand in what way this mutation affected expression of T1F itself as well as other genes across the genome and the E. coli’s virulence and colonization properties. Finally, we will use animal studies to determine the adaptive significance of the T1F and its variants in ST131-H30.