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

基本信息

批准号：
10094178
负责人：
Jimmy D. Ballard
金额：
$ 43.23万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-07 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10094178
关键词：
Accounting Address Anaerobic Bacteria Animal Model Antigen Presentation Antigens Attenuated Bacterial Toxins Binding Biochemical CRISPR/Cas technology Cell Communication Cell Surface Receptors Cells Cessation of life Characteristics Clostridium difficile Complementarity Determining Regions Data Development Disease Endocytosis Endonuclease I Epidemic Frequencies Genes Glucosyltransferase Hamsters Hospitals Human Humoral Immunities Immunologic Memory Immunosuppression In Vitro Infection Intoxication Investigation Knowledge Mediating Memory B-Lymphocyte Molecular Monomeric GTP-Binding Proteins Mutation Pathogenesis Patients Penetration Peptides Proteins Publishing Receptor Cell Relapse Reporting Reproduction spores Research Role Severity of illness System Testing Therapeutic Time Toxic effect Toxin Tropism United States Vaccination Vaccine Antigen Variant Virulence Virulence Factors Work base cell type cytotoxicity experimental study gastrointestinal immunogenicity in vivo inhibitor/antagonist insight mouse model mutant novel pathogen prevent programs receptor receptor binding response tissue tropism

项目摘要

ABSTRACT The most recent reports indicate Clostridioides difficile is the cause of over 400,000 cases of gastrointestinal illness and nearly 30,000 deaths annually. A major factor in the virulence of C. difficile is TcdB, an intracellular bacterial toxin that glucosylates small GTPases in targeted cells. Our studies focus on determining the critical differences in TcdB1 and TcdB2, the two major variants of TcdB. TcdB1 is produced by historical strains of C. difficile and TcdB2 is produced by hypervirulent/epidemic strains of C. difficile. Understanding how these two forms of TcdB, which share 92% identity, differ in critical steps in intoxication and immunogenicity provides insight into underlying differences in virulence between historical and epidemic strains of C. difficile. Several studies, including many from our group, have found that TcdB1 and TcdB2 differ in their interactions with target cells, tropism, cytotoxicity, and immunogenicity. The objective of our work is to identify and characterize the underlying molecular and cellular details of the factors accounting for these differences in TcdB1 and TcdB2 activity. To continue this line of investigation, three specific aims to i) Determine the underlying differences in the molecular mechanism of TcdB1 and TcdB2 receptor binding and cell penetration, ii) Determine if TcdB2 subverts antigen presentation and limits humoral immunity to co-administered vaccine antigen TcdB2Δ1769-1787, and iii) Construct and test strains of C. difficile expressing mutants of TcdB1 and TcdB2 will be pursued. These studies will provide further insight into the differences in TcdB1 and TcdB2, determine the contribution of TcdB to ineffective immune memory leading to relapse, and test hypotheses related to specific TcdB functional activities in the context of C. difficile infection. Overall, the findings from this work will enhance our understanding of C. difficile disease at multiple levels and provide information needed to prevent and treat this serious human illness.

抽象的最新报告表明，艰难梭菌是超过 40 万例病例的病因胃肠道疾病和每年近 30,000 人死亡，这是 C. 艰难梭菌是 TcdB，一种细胞内细菌毒素，可将靶细胞中的小 GTP 酶进行糖基化。我们的重点研究是确定 TcdB1 和 TcdB2 这两个主要的关键差异 TcdB1 是由艰难梭菌的历史菌株产生的，TcdB2 是由艰难梭菌产生的。了解艰难梭菌的高毒力/流行性菌株如何产生这两种形式的 TcdB。具有 92% 的同一性，在中毒和免疫原性的关键步骤上有所不同，提供了深入了解艰难梭菌的历史菌株和流行菌株之间的毒力存在根本差异。研究（包括我们小组的许多研究）发现 TcdB1 和 TcdB2 的不同之处在于与靶细胞的相互作用、趋向性、细胞毒性和免疫原性。是识别和表征因素的潜在分子和细胞细节解释 TcdB1 和 TcdB2 活动的这些差异继续这条线。调查，三个具体目标 i) 确定分子中的根本差异 TcdB1 和 TcdB2 受体结合和细胞渗透的机制，ii) 确定 TcdB2 是否破坏抗原呈递并限制对共同施用的疫苗抗原的体液免疫 TcdB2Δ1769-1787，和iii)构建和测试表达TcdB1突变体的艰难梭菌菌株将继续开展 TcdB2 和 TcdB2 的研究，这些研究将进一步深入了解 TcdB1 的差异。和 TcdB2，确定 TcdB 对无效免疫导致记忆复发的贡献，并测试与艰难梭菌背景下特定 TcdB 功能活动相关的假设总体而言，这项工作的结果将增强我们对艰难梭菌疾病的了解。并提供预防和治疗这种严重的人类疾病所需的信息。