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.

抽象的最近的报告表明，梭状芽胞杆菌艰难梭菌是40万例胃肠道疾病和近30,000例死亡。 C.病毒的主要因素。艰难梭菌是TCDB，这是一种细胞内细菌毒素，可在靶细胞中葡萄糖糖基因葡萄糖。我们的研究重点是确定TCDB1和TCDB2的关键差异，这是两个主要的 TCDB的变体。 TCDB1是由艰难梭菌的历史菌株和TCDB2产生的艰难梭菌过度毒性/流行病。了解这两种形式的TCDB如何共享92％的身份，在中毒和免疫原性方面的关键步骤不同，可洞悉艰难梭菌历史和流行病之间病毒的潜在差异。一些研究，包括我们小组的许多研究，发现TCDB1和TCDB2在其上有所不同与靶细胞，湿气，细胞毒性和免疫原性相互作用。我们工作的目的是识别和表征因子的基本分子和细胞细节考虑到TCDB1和TCDB2活性的这些差异。继续这条线调查，三个特定目标i）确定分子的潜在差异 TCDB1和TCDB2受体结合和细胞渗透机制，ii）确定TCDB2是否是否颠覆抗原表现并将体液免疫学限制为共同采用疫苗抗原 TCDB2Δ1769-1787和iii）艰难梭菌表达TCDB1突变体的构建和测试菌株将追求TCDB2。这些研究将进一步了解TCDB1的差异和TCDB2，确定TCDB对无效的免疫记忆的贡献，导致继电器，并在艰难梭菌中与特定TCDB功能活动有关的测试假设感染。总体而言，这项工作的发现将增强我们对艰难梭菌疾病的理解在多个层面上，提供预防和治疗这种严重人类疾病所需的信息。