Shiga Toxin Production and Role in Pathogenesis

志贺毒素的产生及其在发病机制中的作用

基本信息

批准号：
7364590
负责人：
Alison A. Weiss
金额：
$ 37.3万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7364590
关键词：
Address Adenine Affect Amino Acids Antibiotics Bacteriophages Binding Blood Platelets Cells Cessation of life Cleaved cell Clinical Coagulation Process Colitis Complication Cultured Cells Development Diarrhea Disease Dose Effector Cell Endothelial Cells Escherichia coli EHEC Escherichia coli O157 Event Family Gene Expression Genes Hemolytic-Uremic Syndrome Hybrids Immune In Vitro Incidence Infection Inflammatory Integration Host Factors Intestines Kidney Lead Life Life Cycle Stages Link Lytic Phase Mediator of activation protein Modeling Molecular N glycosidase Papio Pathogenesis Production Protein Biosynthesis RNA, Ribosomal, 28S Recruitment Activity Regulation Research Personnel Ribosomes Role Severity of illness Shiga Toxin Site Thinking Toxic effect Toxin United States Variant Viral Virulence Factors Virus base carbohydrate receptor cytokine globotriaosylceramide in vivo member mouse model mutant neutrophil pathogen programs receptor binding

项目摘要

DESCRIPTION (provided by applicant): E. coli O157:H7 is an emerging pathogen of major importance. Disease caused by E. coli O157:H7 is characterized by diarrhea, hemorrhagic colitis, and the potentially fatal complication, hemolytic uremic syndrome (HUS). Shiga toxin (Stx) is a major virulence factor of E. coli O157:H7. Two major antigenic variants of Shiga toxin, Stx1 and Stx2, share 55% amino acid homology, however Stx2 production has been associated with progression to severe disease, including HUS. We propose to examine two aspects of Shiga toxin in the pathogenesis of disease caused by E. coli O157:H7 - regulation of Shiga toxin production in the intestine and the molecular basis for the difference in potency between Stx1 and Stx2. The genes for Shiga toxin are encoded on bacterial viruses. Regulation of toxin production is strongly linked to factors that affect the virus life cycle, specifically factors that induce the viral lytic cycle, for example antibiotics such as ciprofloxicin. In Specific Aim 1 we will characterize factors that influence Stx2 expression in vitro and in vivo. In addition to amount of toxin production, the type of Shiga toxin produced during infection can influence the severity of disease, with Stx2 being by far the more potent toxin. While it is clear that Stx2 can induce cellular death, it is not clear that cellular death is required for development of HUS, and toxicity may occur at the organismal level. In Specific Aim 2 we will characterize hybrid Stx2/Stx1 mutants to determine why Stx2 is more potent than Stx1 using in vitro cell culture models. In Specific Aim 3 we will determine the potency of the hybrid mutants in vivo using a mouse model of disease. Understanding the viral, bacterial and host factors that influence Shiga toxin production and potency could lead to treatments that reduce the incidence of fatal disease.

描述（由申请人提供）：大肠杆菌O157：H7是一种重要的病原体。大肠杆菌O157：H7引起的疾病的特征是腹泻，出血性结肠炎和潜在的致命并发症，溶血性尿毒症综合征（HUS）。 Shiga毒素（STX）是大肠杆菌O157：H7的主要毒力因子。 Shiga毒素，STX1和STX2的两个主要抗原变异型共享55％的氨基酸同源性，但是STX2的产生与包括HUS在内的严重疾病的发展有关。我们建议在由大肠杆菌O157：H7引起的疾病发病机理中检查志贺毒素的两个方面 - 在肠道中调节志贺毒素的产生以及STX1和STX2之间效力差异的分子基础。志贺毒素的基因在细菌病毒上编码。毒素产生的调节与影响病毒生命周期的因素密切相关，特别是诱导病毒裂解周期的因素，例如抗生素，例如环氧蛋白。在特定目标1中，我们将表征影响体外和体内STX2表达的因素。除了毒素的产生量外，感染过程中产生的志贺毒素类型还会影响疾病的严重程度，而STX2是迄今为止更有效的毒素。虽然很明显，STX2可以诱导细胞死亡，但尚不清楚HUS发育需要细胞死亡，并且在生物水平上可能发生毒性。在特定目标2中，我们将表征混合STX2/STX1突变体，以确定为什么使用体外细胞培养模型比STX1更有效。在特定的目标3中，我们将使用小鼠疾病模型来确定体内杂交突变体的效力。了解影响志贺毒素产生和效力的病毒，细菌和宿主因素可能导致降低致命疾病发生率的治疗。