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)：导管相关性尿路感染(CAUTIs)是最常见的医院感染之一，如果不进行治疗，可能会导致严重的并发症，包括菌血症和死亡。粪肠球菌是CAUTI的主要病原体，其在宿主体内的粘附性和持久性以及多重耐药性使其难以预防和治疗。此外，粪肠球菌可以形成生物膜并生长，尽管在CAUTI期间有强烈的炎症反应。粪肠球菌如何附着、在膀胱中生长、形成生物膜以及生物膜在CAUTI中持续存在的重要性等分子细节尚不清楚。这个项目将使用最近优化的粪肠球菌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导致疾病。需要解决的重要问题包括对毛孔的EBPA亚单位如何与纤维蛋白原结合的分子分析，以及这种相互作用对CAUTI的重要性。体外生物膜形成缺陷突变株完全有能力形成 在小鼠CAUTI中的生物膜，表明标准的生物膜模型不能在体内复制相关的条件。该项目将评估一种新的添加纤维蛋白原的尿液生物膜模型，以确定该模型中生物膜所需的基因是否也是小鼠CAUTI生物膜所必需的，并将测试生物膜在致病中的重要性。最后，我们有数据表明，基于EBPA亚单位的疫苗可以预防小鼠CAUTI，并且免疫的动物会产生阻断EBPA-纤维蛋白原结合的抗体。该项目将测试各种EBPA亚域和多肽疫苗的保护效力，并与使用其他菌毛亚单位的制剂进行比较。结合被动转移免疫动物的血清和抗体反应的特征，将有可能具体测试保护机制是否依赖于阻断EBPA-纤维蛋白原结合。该项目产生的数据将为CAUTI的发病机制提供重要的新见解，并直接应用于开发新的治疗方式。。