TARGETING THE E COLI CHAPERONE SURA IN RECURRENT UTI

针对复发性尿路感染中的大肠杆菌伴侣 SURA

基本信息

批准号：
8168719
负责人：
DAVID ALAN HUNSTAD
金额：
$ 0.97万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-10 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8168719
关键词：
Adhesives Affect Anti-Infective Agents Antibiotic Therapy Antibiotics Biochemical Biological Assay Bladder Bladder Tissue Cell Line Cells Child Chronic Chronic Kidney Failure Collection Communicable Diseases Communities Computer Retrieval of Information on Scientific Projects Database Cystitis Data Development Epithelial Cells Escherichia coli Funding Grant Growth Immune Infection Inflammatory Institution Invaded Knowledge Lead Medical Membrane Modeling Molecular Chaperones Morbidity - disease rate Mus Mutagenesis Oral Outpatients Pain Pathogenesis Pathway interactions Patients Phenotype Pilum Plague Population Production Proteins Recurrence Regimen Research Research Personnel Resources Seeds Source United States United States National Institutes of Health Urinary tract Urinary tract infection Uropathogenic E. coli Virulence Visit Woman Work bacterial resistance cost cytokine extracellular gastrointestinal kidney infection novel pathogen periplasm renal scarring

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Urinary tract infections (UTIs), most commonly caused by uropathogenic Escherichia coli (UPEC), are associated with substantial morbidity and medical cost. Affected women and children are often plagued with recurrences, and repeated infections of the kidney can lead to renal scarring and chronic kidney disease. Recent work in the murine cystitis model has unveiled new paradigms regarding the pathogenesis of UTI. Long thought to be a strictly extracellular pathogen, UPEC has been shown to invade the epithelial cells lining the bladder and to establish large collections, termed intracellular bacterial communities (IBCs), within these cells. UPEC forms a quiescent reservoir within bladder tissue that resists oral antibiotic therapy and is invisible to host immune defenses, a phenotype that may depend on its unique ability to downregulate host inflammatory cytokine production. This bacterial reservoir can then serve as a seed for recurrent infection, a finding that challenges current dogma that recurrent UTI represents re-inoculation of the urinary tract from a gastrointestinal E. coli population. Current antibiotic regimens are challenged by the development of bacterial resistance and do not eradicate the chronic reservoir. Our recent data demonstrate that a conserved periplasmic chaperone called SurA is critical for the production of adhesive type 1 pili, for the UPEC anti-cytokine phenotype, and for intracellular growth of UPEC during IBC maturation. Disruption of SurA function in UPEC also abolishes formation of the quiescent bacterial reservoir. We will employ tagged SurA proteins in a set of biochemical assays to determine the spectrum of outer membrane substrates of this important conserved chaperone in UPEC. Domain complementation and mutagenesis will be performed to delineate the structural features of, and residues within, SurA that are critical for its support of virulence in UPEC. This knowledge will lead to the development of novel anti-infective compounds that target SurA function and interrupt the IBC pathway and the cycle of recurrent UTI. Relevance: Urinary tract infections represent the second most common infectious disease in the United States, with an annual burden of > 7 million outpatient visits and $1 billion in medical cost. Many patients suffer from recurrences that are not only disruptive and painful but can also lead to chronic kidney disease, and current therapies for these patients are insufficient. This proposal identifies a new target for interrupting the cycle of recurrent urinary tract infection.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。尿路感染 (UTI) 最常见是由尿路致病性大肠杆菌 (UPEC) 引起，与大量的发病率和医疗费用相关。受影响的妇女和儿童经常受到复发的困扰，肾脏的反复感染可导致肾脏疤痕和慢性肾脏疾病。最近对小鼠膀胱炎模型的研究揭示了有关尿路感染发病机制的新范例。长期以来，UPEC 被认为是一种严格的细胞外病原体，但它已被证明可以侵入膀胱内壁的上皮细胞，并在这些细胞内建立大量的集合，称为细胞内细菌群落 (IBC)。 UPEC 在膀胱组织内形成一个静态储存库，可以抵抗口服抗生素治疗，并且对宿主免疫防御来说是不可见的，这种表型可能取决于其下调宿主炎症细胞因子产生的独特能力。这种细菌库可以作为复发性感染的种子，这一发现挑战了当前的教条，即复发性尿路感染代表着胃肠道大肠杆菌群对尿道的重新接种。目前的抗生素治疗方案受到细菌耐药性发展的挑战，并且不能根除慢性储存库。我们最近的数据表明，称为 SurA 的保守周质伴侣对于 1 型粘附菌毛的产生、UPEC 抗细胞因子表型以及 IBC 成熟过程中 UPEC 的细胞内生长至关重要。 UPEC 中 SurA 功能的破坏也会消除静止细菌库的形成。我们将在一组生化测定中使用标记的 SurA 蛋白来确定 UPEC 中这一重要保守伴侣的外膜底物谱。将进行结构域互补和诱变来描绘 SurA 的结构特征和残基，这对于支持 UPEC 的毒力至关重要。这些知识将导致新型抗感染化合物的开发，这些化合物以 SurA 功能为目标，并中断 IBC 途径和复发性尿路感染的循环。相关性：尿路感染是美国第二大常见传染病，每年造成超过 700 万人次门诊就诊和 10 亿美元医疗费用。许多患者遭受复发的困扰，这不仅具有破坏性和痛苦，而且还可能导致慢性肾脏病，而目前对这些患者的治疗方法还不够。该提案确定了中断复发性尿路感染循环的新目标。