Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections

产肠毒素大肠杆菌感染的分子发病机制

基本信息

批准号：
8245631
负责人：
James Michael Fleckenstein
金额：
--
依托单位：
MEMPHIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-10-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245631
关键词：
Address Adherence Adhesions Antigens Area Bacteria Bacterial Adhesins Cell Communication Cell Cycle Kinetics Cell Line Cell Surface Receptors Cells Cholera Complex Cytolysis DNA Microarray Chip Data Developed Countries Development Diarrhea Disease Disease Outbreaks Enteral Epithelial Epithelial Cells Escherichia coli Escherichia coli Infections Escherichia coli Vaccines Event Failure Flagella Genes Genetic Transcription Goals Health Heating Heterogeneity Human Image Immune response Infection Intestines Investigation Kinetics Label Laboratories Membrane Methodology Microscopy Molecular Morbidity - disease rate Nature New Agents Organism Pathogenesis Plasmids Prevention Prevention approach Proteins Pseudomonas Research Role Soldier Structure Surface Toxin Translating United States Urinary tract infection Vaccines Veterans Virulence Virulence Factors design enteric pathogen enterotoxigenic Escherichia coli fimbria foodborne outbreak global health immunogenic insight mortality novel novel strategies pathogen pathogenic Escherichia coli public health relevance release factor research and development response time use tool vaccine development

项目摘要

DESCRIPTION (provided by applicant): The enterotoxigenic Escherichia coli (ETEC) are a genetically diverse type of pathogenic E. coli that cause astounding numbers of cases of diarrheal illness worldwide, and have emerged as a cause of large-scale outbreaks of diarrhea in the United States. These organisms share the ability to produce, secrete, and deliver heat-stable (ST) and/or heat-liable (LT) toxins to the intestinal lining cells ultimately causing diarrhea, which can be severe and cholera-like. The toxin genes encoded on plasmids, were identified shortly after the discovery of these toxin-producing E. coli more than 40 years ago. Most research on ETEC until very recently focused on a small number of molecules, namely the toxins themselves and plasmid-encoded fingerlike colonization factors (CFs). Unfortunately, vaccine development centered on these antigens alone has proven to be very challenging in part because of the heterogeneity of the CF molecules and the fact that the toxins do not appear to afford complete protection against disease (in the case of LT), or are not immunogenic (as is the case for ST). The recent failure of several vaccines incorporating these antigens has prompted both a search for alternative strategiesand a return to basic pathogenesis studies in order to address gaps in our understanding of how these globally important pathogens cause disease. While much is known about the molecular action of these toxins once they enter host cells, very little is known about how the bacteria effectively deliver these toxins to their respective cell surface receptors. These studies will use recently developed molecular tools, capitalize on recent discoveries of new agents, and exploit the state-of-the-art methodology to define the roll of novel molecules on the surface of ETEC that promote the effective delivery of these toxins. The long-term goal of these studies is to translate this information into rational design of a safe, effective, and broadly protective ETEC vaccine.

描述（由申请人提供）：肠毒素大肠杆菌（ETEC）是一种遗传多样的致病性大肠杆菌，引起了全球腹泻疾病的惊人数量，并且已成为美国腹泻大规模爆发的原因。这些生物具有产生，分泌和输送热稳定（ST）和/或热易生（LT）毒素的能力，最终会引起腹泻，这可能是严重且类似霍乱的。在40多年前发现这些产生这些毒素的大肠杆菌后不久，在质粒上编码的毒素基因被鉴定出来。直到最近，大多数对ETEC的研究都集中在少数分子上，即毒素本身和质粒编码的鱼种定植因子（CFS）。不幸的是，仅仅以这些抗原为中心的疫苗开发被证明是非常具有挑战性的，部分原因是CF分子的异质性以及毒素似乎没有完全保护疾病的完全保护（在LT的情况下），或者没有免疫原性（与ST一样）。纳入这些抗原的几种疫苗最近发生的销售既促使人们既寻求替代策略，又恢复了基本的发病机理研究，以解决我们对这些全球重要病原体如何引起疾病的理解的差距。尽管这些毒素进入宿主细胞的分子作用知之甚少，但对于细菌如何有效地将这些毒素传递到其各自的细胞表面受体的情况下，知之甚少。这些研究将使用最近开发的分子工具，利用新药物的最新发现，并利用最先进的方法来定义ETEC表面上新型分子的卷，以促进这些毒素的有效递送。这些研究的长期目标是将这些信息转化为安全，有效和广泛保护性ETEC疫苗的合理设计。