Delineating the importance of intracellular tissue occupation by Uropathogenic E.

描述尿路致病性大肠杆菌占据细胞内组织的重要性。

基本信息

批准号：
8703685
负责人：
DREW Joel SCHWARTZ
金额：
$ 3.84万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-05-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703685
关键词：
Accounting Acute Address Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteria Bacterial Infections Bacteriuria Biological Markers Biological Response Modifiers Bladder Cells Cessation of life Chemicals Chronic Chronic Cystitis Clinical Coitus Communities Complex Cystitis Cytoplasm Data Defense Mechanisms Development Disease Disease Outcome Elements Environment Epithelial Epithelial Cells Epithelium Event Female Filament Frequencies Goals Health Care Costs Hour Human Immune response Immune system Immunologic Receptors Infection Invaded Kidney Lead Microbial Biofilms Microscopy Modeling Molecular Morbidity - disease rate Multi-Drug Resistance Mus Mutant Strains Mice Occupations Operative Surgical Procedures Organelles Organism Outcome Pathogenesis Pilum Population Process Public Health Pyelonephritis Recurrence Research Risk Factors Role Sepsis Staging Surface Time Tissues Transcend Ureter Urinary tract Urinary tract infection Urination Urine Uropathogen Uropathogenic E. coli Vacuole Virulent Woman experience extracellular in vivo inhibitor/antagonist mouse model mutant neutrophil new therapeutic target nosocomial UTI novel therapeutics pathogen prevent research study response toll-like receptor 4 two-photon

项目摘要

DESCRIPTION (provided by applicant): Urinary tract infections (UTIs) are among the most common bacterial infections, accounting for tremendous morbidity and healthcare costs. Up to 60% of women will experience a UTI in her lifetime, with between 25 and 40% of these women suffering frequent recurrences, recalcitrant to antibiotic therapy. More than 80% of community acquired and 50% of nosocomial UTIs are caused by uropathogenic E. coli (UPEC). The pathogenesis of UTI is complex with UPEC capable of colonizing multiple niches within the bladder and the kidneys. UPEC utilize surface expressed extracellular organelles known as type 1 pili to attach to, invade, and replicate within the terminally differentiated superficial facet clls in the bladder epithelium. UPEC escape the endocytic vacuole and replicate in cytoplasm into large biofilm-like masses called intracellular bacterial communities (IBCs). Within this environment, UPEC replicate rapidly and are protected from elements of the innate immune response as well as clearance by micturition. Furthermore, UPEC within IBCs are resistant to antibiotic therapy that is otherwise effective against the organisms grown in broth culture. Formation of IBCs is essential for bacterial colonization of the bladder in mouse models, and IBCs have been detected in urine from women suffering recurrent UTI. Understanding the pathogenesis of UPEC with regard to its ability to invade and replicate intracellularly is paramount to identifying targets for novel therapeutics that prevent bladder invasion and persistence. Recent data suggests that the formation of IBCs within the first 24 hours after experimental inoculation of bacteria into the murine urinary tract constitutes a robust population bottleneck restricting bacterial diversity progressing to later stages of infection. Furthermore, during this same time period, the induction of a robust immune response predisposes mice to experience persistent bacteriuria and chronic cystitis. This proposal explores the hypothesis that occupation of an intracellular niche during acute infection directly leads to an immune response predisposing the host to persistent bacteriuria and recurrent/chronic cystitis. Utilizing a well- characterized murine model of UTI, the molecular mechanisms accounting for the dramatic bottleneck during acute UTI, the direct relationship between acute pathogenic events and long-term UTI outcome, and the impact of sequential bladder inoculation on infection will be determined. The objectives of this research are to investigate the key events during acute UTI pathogenesis that impact infection outcome. Completion of this research will help to identify key events in pathogenesis that can be targeted with novel therapeutics to limit the morbidity of UTI.

描述（由申请人提供）：尿路感染（UTI）是最常见的细菌感染之一，占据了巨大的发病率和医疗保健费用。多达60％的妇女在她的一生中会经历UTI，其中25％至40％的女性经常复发，对抗生素疗法进行了顽固的复发。超过80％的社区被收购和50％的医院UTI是由尿液发育大肠杆菌（UPEC）引起的。 UTI的发病机理很复杂，UPEC能够在膀胱和肾脏内定植多个壁ni。 UPEC利用表面表达的细胞外细胞器被称为1型pili，可与膀胱上皮的终端分化的浅表面CLL相连，侵入和复制。 UPEC逃脱了内吞液泡，并在细胞质中复制成称为细胞内细菌群落（IBC）的大型生物膜样质量。在这种环境中，UPEC会迅速复制，并受到先天免疫反应的元素以及预防量的清除。此外，IBC中的UPEC对抗生素疗法具有抵抗力，否则对肉体培养物中生长的生物有效。 IBC的形成对于小鼠模型中膀胱的细菌定植至关重要，并且在患有复发性UTI的妇女的尿液中发现了IBC。了解UPEC的发病机理在其侵入和细胞内复制的能力是确定防止膀胱侵袭和持久性的新型治疗剂的靶标。最近的数据表明，在将细菌接种到鼠泌尿道中的最初24小时内，IBC的形成构成了强大的种群瓶颈，限制了细菌多样性发展到后来的感染阶段。此外，在同一时期，稳健的免疫反应的诱导使小鼠容易经历持续的杆菌和慢性膀胱炎。该提案探讨了以下假设：急性感染期间细胞内小裂的占用直接导致免疫反应诱发宿主持续存在的细菌和复发/慢性/慢性膀胱炎。利用一个良好的特征性鼠模型，急性UTI期间急剧瓶颈的分子机制，急性致病事件与长期UTI结局之间的直接关系以及顺序接种对感染的影响。这项研究的目标是研究影响感染结果的急性UTI发病机理中的关键事件。这项研究的完成将有助于确定发病机理中的关键事件，这些事件可以针对新型的治疗剂来限制UTI的发病率。