Optimization of protective antibodies response against bacterial adhesins

摘要 这项建议的主要目标是了解主要致病机制的构象特性 大肠杆菌因子--最常见的一种大肠杆菌菌毛粘附素--定义了其诱导保护性 抗体反应作为预防大肠杆菌引起的尿路感染的候选疫苗。FimH是一个 是1型菌毛的粘附亚单位，是影响大肠杆菌结合人的能力的主要因素之一 尿路上皮并引起尿路感染。我们确定了FimH的甘露糖结合凝集素结构域 可以呈现两种构象状态-对末端暴露的甘露糖具有高亲和力和低亲和力 残留物。FimH的构象变化本质上是高度动态的，是FimH能力的基础 介导剪切增强的细菌黏附，快速而强烈地结合人类细胞受体和脱落结合 抗体。我们打算对这两种抗体进行全面的功能分析 从免疫的角度分析FimH的构象变化 对黏附蛋白的反应。

ABSTRACT The primary goal of this proposal is to understand how conformational properties of the major pathogenesis factor of E. coli - most common, type 1 fimbrial adhesin of E. coli - defines its ability to elicit a protective antibody response as a vaccine candidate against urinary tract infections caused by E. coli. FimH is an adhesive subunit of the type 1 fimbriae and is one of the major factors in the ability of E. coli to bing human urothelium and cause urinary tract infection. We determined that the mannose-binding lectin domain of FimH can assume two conformational states - with a high- and low-affinity towards terminally-exposed mannosyl residues. The conformational shift in FimH is highly dynamic in nature and is the basis of the ability of FimH to mediate shear-enhanced bacterial adhesion, bind fast and strongly human cell receptors and shed bound antibodies. We intend to perform a comprehensive functional analysis of antibodies against both conformational states of FimH to analyze the conformational switch in FimH in the context of the immune response against the adhesive protein.