Optimization of protective antibodies response against bacterial adhesins

摘要 该建议的主要目标是了解主要发病机制的构象特性 因子E.大肠杆菌-最常见的，大肠杆菌的1型菌毛粘附素。大肠杆菌-定义了它的能力， 抗体反应作为疫苗候选人对尿路感染引起的E。杆菌FimH是一个 1型菌毛的粘附亚基是影响E.大肠杆菌感染人 尿道炎并引起尿路感染。我们确定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基具有高亲和力和低亲和力 残基FimH中的构象转变在本质上是高度动态的，并且是FimH能够在分子水平上改变构象的基础。 介导剪切增强的细菌粘附，结合快速和强烈的人细胞受体和脱落结合 抗体的我们打算对这两种抗体进行全面的功能分析， FimH的构象状态，以分析免疫背景下FimH中的构象转换 对粘附蛋白的反应。

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.