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）：在发达国家，艰难梭菌是医院获得性疾病的主要原因，抗生素耐药性、复发（RCDI）和产生高毒力的新菌株的高毒力使艰难梭菌感染（CDI）的治疗变得复杂。 TcdB 的毒性变体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，实验将描述其特征。 TcdB (TcdB1) 的历史形式和较温和的形式与高毒性 TcdB2 之间的差异表明，TcdB2 比 TcdB1 具有更广泛的趋向性并且细胞毒性更强。此外，TcdB1 的抗体不会交叉中和。 TcdB2，表明当前针对 TcdB 的疫苗和治疗抗体可能无法针对多种艰难梭菌菌株提供广泛的保护。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，并影响 RCDI 的差异。 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 掩盖本项目目标 3 中的中和表位的机制。将确定 TcdB1 和 TcdB2 的差异如何使患者易患 RCDI。该项目的结果将提供第一个见解。研究 TcdB1 和 TcdB2 的不同作用，以及 TcdB2 的呼吸毒性和抗原性改变对艰难梭菌高毒力菌株出现的影响。