EBPA-FIBROGEN INTERACTION IN ENTEROCOCCUS FAECALIS CAUTI

粪肠球菌中 EBPA-纤维原的相互作用

• 批准号: 8901925
• 负责人: Michael G. Caparon
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901925
• 关键词: Address; Adherence; Adhesives; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Response; Bacteremia; Bacteria; Bacterial Adhesins; Binding; Biogenesis; Biological Assay; Biology; Bladder; Bladder Tissue; Blocking Antibodies; Catheters; Cessation of life; Collaborations; Data; Development; Disease; Drug Formulations; Endocarditis; Enterococcus faecalis; Epithelium; Fibrinogen; Genes; Growth; Hair; Health; Immunity; Immunization; Immunotherapy; In Vitro; Infection; Inflammatory Response; Interferometry; Kinetics; Lead; Ligand Binding; Microbial Biofilms; Modality; Modeling; Molecular; Molecular Analysis; Mus; Mutagenesis; Nosocomial Infections; Nutritional Requirements; Passive Immunization; Pathogenesis; Patients; Peptide Vaccines; Peptides; Pilum; Platinum; Proliferating; Protein Region; Proteins; Resistance; Serum; Silicones; Site-Directed Mutagenesis; Specificity; Testing; Therapeutic Agents; Thermodynamics; Tube; Urethra; Urinary Catheterization; Urinary tract; Urinary tract infection; Urine; Vaccines; Virulence; alternative treatment; appendage; bacterial resistance; base; catheter associated UTI; direct application; human disease; implantation; in vitro Assay; in vivo; insight; interdisciplinary approach; mouse model; mutant; novel; novel therapeutics; prevent; protective efficacy

DESCRIPTION (provided by applicant): Catheter-associated urinary tract infections (CAUTIs) are one of the most common nosocomial infections and if untreated can lead to serious complications including bacteremia and death. Enterococcus faecalis is a leading causative agent of CAUTI and its ability to adhere and persist within the host along with its multiple antibiotic resistances makes it difficult to prevent and treat. Furthermore, E. faecalis can form biofilm and grow despite a robust inflammatory response during CAUTI. The molecular details of how E. faecalis adheres, grows in the bladder, forms biofilm and the importance of biofilm in persistence in CAUTI are not well understood. This project will use a recently optimized model of E. faecalis CAUTI to understand how interactions between the E. faecalis Epb pilus and fibrinogen contribute to disease. Important questions to be addressed include a molecular analysis of how the EbpA subunit of the pilus binds to fibrinogen and the importance of this interaction to CAUTI. Mutants defective for biofilm formation in vitro are fully capable of forming biofilm in murine CAUTI, suggesting that standard biofilm models do not reproduce relevant in vivo conditions. This project will evaluate a new model of fibrinogen-supplemented urine biofilms to determine if genes required for biofilm in this model are also required for biofilm in murine CAUTI and will test the importance of biofilm in causing disease. Finally, we have data to suggest that an EbpA subunit-based vaccine protects against murine CAUTI and that immunized animals generate antibody that blocks EbpA-fibrinogen binding. The project will test the protective efficacy of various EbpA sub-domain and peptide vaccines in comparison to formulations that use other pilus sub- units. Combined with passive transfers of sera from immunized animals and characterization of antibody responses, it will be possible to specifically test whether the mechanism of protection depends on blocking EbpA-fibrinogen binding. The data generated by this project will provide significant new insights into the pathogenesis of CAUTI with direct application to the development of new modalities of therapy. .

描述（由申请人提供）：与导管相关的尿路感染（CAUTIS）是最常见的医院感染之一，如果未治疗，可能会导致严重的并发症，包括菌血症和死亡。肠球菌粪便是Cauti的领先病因及其在宿主中粘附和持续及其多种抗生素抗性的能力，因此难以预防和治疗。此外，尽管在小肠期间有强大的炎症反应，但粪肠球菌可以形成生物膜并生长。大肠杆菌如何粘附在膀胱中生长，形成生物膜以及生物膜在牛uti持续的重要性的分子细节尚不清楚。该项目将使用最近优化的粪肠球菌小肠模型来了解粪肠球菌EPB菌毛和纤维蛋白原之间的相互作用如何有助于疾病。要解决的重要问题包括分子分析菌毛的EBPA亚基与纤维蛋白原的结合以及这种相互作用对CAUTI的重要性。体外生物膜形成有缺陷的突变体完全能够形成 鼠类小叶中的生物膜，表明标准生物膜模型在体内条件下不会再现相关。该项目将评估纤维蛋白原补充的尿液生物膜的新模型，以确定该模型中生物膜在鼠Cauti中也需要生物膜中所需的基因，并将测试生物膜在引起疾病中的重要性。最后，我们有数据表明，基于EBPA亚基的疫苗可以保护鼠类小肠，并且免疫动物会产生阻断EBPA-纤维蛋白原结合的抗体。与使用其他Pilus子单位的制剂相比，该项目将测试各种EBPA亚域和肽疫苗的保护性疗效。结合免疫动物的血清的被动转移和抗体反应的表征，可以专门测试保护机理是否取决于阻断EBPA-纤维蛋白原结合。该项目产生的数据将为Cauti的发病机理提供重要的新见解，直接应用于新的治疗方式。 。