SHIGELLA TOXIN; STRUCTURE & FUNCTION RELATIONSHIPS

志贺氏菌毒素；

• 批准号: 3129924
• 负责人: ARTHUR M. DONOHUE-ROLFE
• 金额: $ 18.56万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3129924
• 关键词: Escherichia coli; Shigella dysenteriae; antibody specificity; antigen receptors; bacillary dysentery; bacterial genetics; bacterial toxins; binding proteins; chemical binding; cross immunity; gene mutation; genetic manipulation; genetic strain; glycoproteins; laboratory mouse; laboratory rabbit; monoclonal antibody; nitrosoguanidines; protein biosynthesis; protein structure function

Shigellosis is a world wide disease producing significant morbidity and in developing countries, a leading cause of diarrheal disease mortality. The Shigella species which causes the severest disease, dysenteriae, produces a potent toxin molecule which inhibits protein synthesis. The toxin consists of one A chain and 5 B chains. A functional role of the B chain is to mediate toxin binding to the eukaryotic cell surface. The toxin receptors are glycolipids containing terminal Gal-alpha1->4Gal disaccharide. Shiga toxin is now considered to be the prototype of a family of toxins which have been called Shiga-like. Shiga and Shiga-like toxins are associated with many clinical manifestations including diarrhea, dysentery, hemorrhagic colitis, and the hemolytic uremic syndrome. This proposal is designed to study basic structure-function relationship of the toxin B chain. A monoclonal antibody which cross-reacts with the B chain of Shiga and Shiga-like toxin II will be characterized. Since these two toxins are thought to be immunologically distinct and since the two bind to an identical set of receptors, particular attention will be focused on whether this antibody is directed against the binding domain. A monoclonal antibody and a glycoprotein with Gal-alpha1->4Gal terminal disaccharide, P1-glycoprotein, will be used as tools to select bacterial strains which produce B subunits with binding domain alterations. The characterization of these mutants will provide an understanding of the regions of the B chain involved in receptor recognition. This information will be useful for the future design of safe and effective vaccines and for the potential design of therapeutic intervention regimens. Additionally the biochemical and genetic characterization of a material which cross- reacts with antibody against Shiga toxin will be undertaken with particular emphasis on revealing the role this material may play in pathogenesis. Finally, the uncharacterized cytotoxins produced by other Gram-negative organisms will be analyzed for their Shiga-like properties. Information as to whether other pathogenic bacteria produce Shiga-like toxins will aid in our understanding of the spectrum of disease associated with toxin.

志贺氏菌病是一种世界范围的疾病，发病率很高， 发展中国家，腹泻病是导致死亡的主要原因。 这 志贺氏菌属引起最严重的疾病，即痢疾，产生一种 抑制蛋白质合成的强效毒素分子。 该毒素由 1条A链和5条B链。 B链的一个功能作用是 介导毒素与真核细胞表面的结合。 毒素受体 是含有末端 Gal-alpha1->4Gal 二糖的糖脂。 滋贺县 毒素现在被认为是毒素家族的原型， 被称为志贺样。 志贺毒素和志贺样毒素相关 具有多种临床表现，包括腹泻、痢疾、 出血性结肠炎和溶血性尿毒症综合征。 该提案旨在研究基本的结构-功能关系 毒素B链。 A 与 B 发生交叉反应的单克隆抗体 志贺毒素和志贺样毒素 II 链将得到表征。 由于这些 两种毒素被认为在免疫学上是不同的，并且由于这两种毒素 与一组相同的受体结合，特别注意 关于该抗体是否针对结合域。 一个 单克隆抗体和具有 Gal-alpha1->4Gal 末端的糖蛋白 二糖，P1-糖蛋白，将被用作选择细菌的工具 产生具有结合域改变的B亚基的菌株。 这 这些突变体的表征将提供对 B 链区域参与受体识别。 此信息 将有助于未来设计安全有效的疫苗 治疗干预方案的潜在设计。 此外 材料的生化和遗传特征 与志贺毒素抗体发生反应将进行特殊处理 强调揭示这种物质在发病机制中可能发挥的作用。 最后，其他革兰氏阴性菌产生的未表征的细胞毒素 将分析生物体的志贺样特性。 信息为 其他致病菌是否产生志贺样毒素将有助于 我们对与毒素相关的疾病谱的了解。