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Structural Mechanisms of Clostridioides difficile pathogenesis

艰难梭菌发病机制的结构机制

基本信息

批准号：
10620653
负责人：
Dana Borden Lacy
金额：
$ 51.86万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620653
关键词：
Anaerobic Bacteria Animals Apical Apoptosis Avidity Bacteria Binding Binding Sites Brush Border Cell Line Cell model Cell surface Cells Cellular Tropism Centers for Disease Control and Prevention (U.S.)Cessation of life Chondroitin Sulfate Proteoglycan Clinical Clostridium difficile Colon Communities Complex Cryoelectron Microscopy Data Development Diarrhea Disease Enzymes Epidemic Epithelium Etiology FZD1 gene Family Funding Glucosyltransferase Goals Guanosine Triphosphate Phosphohydrolases Hospitalization Hospitals Human Incidence Infection Infection prevention Inflammation Intestines Intoxication Life Link Location Mediating Modeling Molecular Mus Mutagenesis Mutation PDGF receptor tyrosine kinase Pathogenesis Patients Persons Physiological Platelet-Derived Growth Factor Receptor Play Prevention Prevention strategy Production Proteins Pseudomembranous Colitis Public Health Reporting Reproduction spores Research Resolution Ribotypes Role Site-Directed Mutagenesis Stromal Cells Structure Surface Symptoms Technology Testing Therapeutic Therapeutic Intervention Tissue Model Tissues Toxic Megacolon Toxin Tropism United States Vaccines Variant Villus Virulence Factors Work antibiotic-associated diarrhea cell type cytokine design experience experimental study human disease in vivo intestinal crypt light microscopy member microscopic imaging molecular imaging mouse model mutant nectin novel novel therapeutics poliovirus receptor predictive tools programs receptor receptor binding receptor function recurrent infection response rho structural biology targeted treatment

项目摘要

Summary Clostridioides difficile is a Gram-positive, spore-forming anaerobe that infects the colon, causing a range of human disease including diarrhea, pseudomembranous colitis, and toxic megacolon. The United States Centers for Disease Control reports that, in 2017, there were 223,900 estimated cases of C. difficile infection (CDI) in hospitalized patients in the United States with an estimated 12,800 deaths. The incidence of community- acquired CDI is also common making C. difficile a significant public health concern. The bacterium makes a toxin, TcdB, which is responsible for the majority of CDI symptoms. The goal of the proposed project is to define the structural basis and physiologic consequences of TcdB binding to receptor proteins on the host cell surface. In Aim 1, we will define the structures and key residues involved in TcdB-receptor interactions using a combination of structural biology, mutagenesis, and quantitative binding approaches. We will use this information to generate C. difficile strains with defined mutations in TcdB receptor binding sites. In Aim 2, we will evaluate the cellular tropism of the toxin in the context of a human explant intoxication model, taking advantage of significant technological advances in high resolution light microscopy imaging. These studies will be paired with mechanistic studies in a novel cellular model of TcdB intoxication as well as the mouse model of CDI. Collectively, these studies will define the physiologic consequences associated with defined TcdB-receptor interactions and are expected to provide a mechanistic framework for advancing novel therapeutic and CDI prevention strategies.

概括艰难梭菌是一种革兰氏阳性、形成孢子的厌氧菌，可感染结肠，引起一系列人类疾病包括腹泻、伪膜性结肠炎和中毒性巨结肠。美国中心疾病控制报告称，2017 年，估计有 223,900 例艰难梭菌感染 (CDI) 病例美国住院患者估计有 12,800 人死亡。社区发病率—— 获得性 CDI 也很常见，这使得艰难梭菌成为一个重大的公共卫生问题。细菌会产生毒素， TcdB，它是造成大多数 CDI 症状的原因。拟议项目的目标是定义 TcdB 与宿主细胞表面受体蛋白结合的结构基础和生理后果。在目标 1，我们将使用组合来定义参与 TcdB-受体相互作用的结构和关键残基结构生物学、诱变和定量结合方法。我们将使用这些信息来生成 TcdB 受体结合位点具有确定突变的艰难梭菌菌株。在目标 2 中，我们将评估细胞在人类外植体中毒模型的背景下毒素的向性，利用显着的优势高分辨率光学显微镜成像的技术进步。这些研究将与 TcdB 中毒的新型细胞模型以及 CDI 小鼠模型的机制研究。总的来说，这些研究将定义与特定 TcdB 受体相互作用相关的生理后果，预计将为推进新型治疗和 CDI 预防策略提供机制框架。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clostridium sordellii Lethal-Toxin Autoprocessing and Membrane Localization Activities Drive GTPase Glucosylation Profiles in Endothelial Cells.

DOI：
10.1128/msphere.00012-15
发表时间：
2016-01
期刊：
mSphere
影响因子：
4.8
作者：
Craven R;Lacy DB
通讯作者：
Lacy DB

Clostridium difficile Toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism.

DOI：
10.1371/journal.ppat.1003072
发表时间：
2012
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Chumbler NM;Farrow MA;Lapierre LA;Franklin JL;Haslam DB;Goldenring JR;Lacy DB
通讯作者：
Lacy DB

Toward a structural understanding of Clostridium difficile toxins A and B.