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（由申请人提供）：艰难梭菌是发达国家医院获得性疾病的主要原因。艰难梭菌感染 (CDI) 的治疗因抗生素耐药性、复发 (RCDI) 以及产生 TcdB 剧毒变体的新兴菌株的高毒力而变得复杂。 TcdB 是艰难梭菌的主要毒力因子，可导致胃肠道损伤、炎症和全身损伤。在这些研究中，实验将描述历史上较温和的 TcdB (TcdB1) 与剧毒 TcdB2 之间的差异。我们小组已发表的初步数据表明，TcdB2 比 TcdB1 具有更广泛的趋向性和更强的细胞毒性。此外，TcdB1 抗体不会交叉中和 TcdB2，这表明当前针对 TcdB 的疫苗和治疗性抗体可能无法针对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，以确定它们如何影响细胞中毒、抗原性和 RCDI。目标 1 将描述差异的特征 TcdB1 和 TcdB2 之间的双受体相互作用，评估其如何影响内吞作用，并确定影响这些事件的关键残基。目标 2 将探索 TcdB2 隐藏中和表位的机制，否则这些表位会在 TcdB1 中暴露。该项目目标 3 的实验将确定 TcdB1 和 TcdB2 的差异如何使患者容易患 RCDI。该项目的结果将首次深入了解 TcdB1 和 TcdB2 的不同作用，以及 TcdB2 的毒性增强和抗原性改变对艰难梭菌高毒力菌株出现的影响。