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Optimization of protective antibodies response against bacterial adhesins

针对细菌粘附素的保护性抗体反应的优化

基本信息

批准号：
10731509
负责人：
Mark Cartwright
金额：
$ 31.11万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-18 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731509
关键词：
Adhesives Affect Affinity Antibodies Antibody Repertoire Antibody Response Antimicrobial Resistance Attention Bacteria Bacterial Adhesins Bacterial Adhesion Bacterial Infections Binding Biocompatible Materials Black race Cell Adhesion Cell-Matrix Junction Cells Code Color Communities Cystitis Effectiveness Elderly Engineering Epitopes Escherichia coli Escherichia coli Adhesins Fimbriae Proteins Fimbrial Adhesins Goals Human Immune response Immunity Immunoglobulin G Infant Infection Invaded Journals Lectin Ligands Mannose Mannose Binding Lectin Maps Mediating Medicine Microbial Biofilms Microbiology Molecular Molecular Analysis Molecular Biology Molecular Conformation Monoclonal Antibodies Morbidity - disease rate Multi-Drug Resistance Nature Passive Immunization Pathogenesis Pilum Population Property Proteins Public Health Pyelonephritis Receptor Cell Specificity Structure Testing Universities Urinary tract infection Uropathogenic E. coli Urothelium Vaccinated Vaccination Vaccine Design Vaccines Virus Diseases Washington antibiotic resistant infections conformer fimbria in vivo mannose receptor mortality mouse model neutralizing antibody nosocomial UTI novel strategies pathogenic bacteria pathogenic microbe polyclonal antibody response type 1 fimbriae urovirulent isolates vaccine candidate vaccine development young woman

项目摘要

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.

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。