Differential Effects of TcdB1 and TcdB2 in C. difficile disease

TcdB1 和 TcdB2 在艰难梭菌疾病中的不同作用

• 批准号: 8945312
• 负责人: Jimmy D. Ballard
• 金额: $ 18.5万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-07 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8945312
• 关键词: Accounting; Address; Antibiotic Resistance; Antibodies; Cells; Characteristics; Clostridium difficile; Data; Developed Countries; Disease; Disease Outcome; Endocytosis; Epitopes; Event; Health; Homologous Gene; Hospitals; Human; Immune; Immune response; Immunity; In Vitro; Infection; Inflammation; Intoxication; Maps; Molecular; Patients; Production; Publishing; Recurrence; Research; Therapeutic; Therapeutic antibodies; Tissues; Toxic effect; Toxin; Tropism; Vaccines; Variant; Virulence; Virulence Factors; Virulent; base; cytotoxic; cytotoxicity; experience; gastrointestinal; in vivo; insight; mortality; neutralizing antibody; pathogen; prevent; public health relevance; receptor; receptor binding; research study; tissue tropism

 DESCRIPTION (provided by applicant): Clostridium difficile is a leading cause of hospital-acquired illness in developed countries. Treating C. difficile infection (CDI) is complicated by antibiotic resistance, recurrence (RCDI), and hypervirulence of emerging strains that produce a highly toxic variant of TcdB. TcdB is a major C. difficile virulence factor that contributes to gastrointestinal damage, inflammation, and systemic damage. In these studies experiments will characterize the differences between the historical and milder form of TcdB (TcdB1) and the hypertoxic TcdB2. Published and preliminary data from our group shows that TcdB2 has a broader tropism and is more cytotoxic than TcdB1. In addition, antibodies to TcdB1 do not cross-neutralize TcdB2, suggesting that current vaccines and therapeutic antibodies targeting TcdB may not provide broad protection against multiple strains of C. difficile. The study will examine molecular differences between TcdB1 and TcdB2 to determine how these impact cellular intoxication, antigenicity, and influence RCDI. Aim 1 will characterize the differences in dual-receptor interactions between TcdB1 and TcdB2, assess how this impacts endocytosis, and identify key residues that influence these events. Aim 2 will explore a mechanism through which TcdB2 cloaks neutralizing epitopes which are otherwise exposed in TcdB1. Experiments in aim 3 of this project will determine how the differences in TcdB1 and TcdB2 predispose patients to RCDI. The results from this project will provide the first insights into the differentil effects of TcdB1 and TcdB2 and the impact of TcdB2's heightened toxicity and altered antigenicity on the emergence of hypervirulent strains of C. difficile.

 描述（由适用提供）：艰难梭菌是发达国家医院获得疾病的主要原因。治疗艰难梭菌感染（CDI）因抗生素耐药性，复发性（RCDI）和产生TCDB剧毒变体的新出现菌株的过度投资而变得复杂。 TCDB是​​艰难梭菌病毒的主要因素，导致胃肠道损伤，感染和全身损害。在这些研究中，实验将表征TCDB（TCDB1）与莫勒（TCDB1）的历史和米勒形式之间的差异。来自我们小组的发布和初步数据表明，TCDB2比TCDB1更广泛，并且具有更大的细胞毒性。此外，对TCDB1的抗体不会跨中和TCDB2，这表明靶向TCDB的当前疫苗和治疗性抗体可能无法为多种艰难梭菌菌株提供广泛的保护。该研究将检查TCDB1和TCDB2之间的分子差异，以确定这些如何影响细胞中毒，抗原性和影响RCDI。 AIM 1将表征 TCDB1和TCDB2之间的双受体相互作用，评估这如何影响内吞作用，并确定关键保留影响这些事件的关键。 AIM 2将探索一种机制，TCDB2披风中和表位，否则在TCDB1中暴露了。该项目的AIM 3中的实验将决定TCDB1和TCDB2患者对RCDI的差异。该项目的结果将为TCDB1和TCDB2的区分效应以及TCDB2的毒性升高和抗原性改变对艰难梭菌菌株出现的毒性增强和改变的影响提供第一个见解。