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

摘要 粘连是泌尿道感染和肠道感染发病的基本特征。 定殖E.大肠杆菌和甘露糖特异性1型菌毛（T1 F）是最关键的粘附因子。我们 目的是了解大流行性尿路致病性克隆组T1 F中的一些独特特征， ST 131-H30适应于该亚克隆的尿毒力和肠道适应性。我们将集中精力 菌毛甘露糖结合粘附亚基FimH和FimH的结构-功能分析 菌毛表达的调节机制，特异于ST 131-H30。我们将以伟大的 通过比较其介导粘附的能力，详细描述了菌毛粘附素FimH的功能特性 在各种流动和抑制条件下。我们还将确定基因的功能意义， 插入使编码T1 F的正调节因子FimB的基因失活。我们将尝试 了解这种突变以何种方式影响T1 F本身以及其他基因的表达。 基因组和E.大肠杆菌的毒力和定殖特性。最后，我们将使用动物研究， 确定ST 131-H30中T1 F及其变体的适应性意义。

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.