Delineating the importance of intracellular tissue occupation by Uropathogenic E.

描述（由申请人提供）：尿路感染（UTI）是最常见的细菌感染之一，造成了巨大的发病率和医疗保健成本。高达60%的女性在一生中会经历UTI，其中25%至40%的女性经常复发，对抗生素治疗无效。超过80%的社区获得性和50%的医院获得性尿路感染是由尿路致病性大肠杆菌引起的。大肠杆菌（UPEC）。UTI的发病机制是复杂的，UPEC能够在膀胱和肾脏内的多个小生境中定植。UPEC利用称为1型皮利的表面表达的细胞外细胞器附着、侵入膀胱上皮中的终末分化的浅表小面细胞并在其中复制。UPEC逃离内吞空泡并在细胞质中复制成称为细胞内细菌群落（IBC）的大型生物膜样团块。在这种环境中，UPEC快速复制，并受到保护，免受先天免疫反应的影响，以及通过排尿清除。此外，IBC内的UPEC对抗生素治疗具有抗性，否则抗生素治疗对肉汤培养物中生长的生物体有效。IBC的形成对于小鼠模型中膀胱的细菌定殖是必不可少的，并且已经在患有复发性UTI的女性的尿液中检测到IBC。了解UPEC的发病机制及其在细胞内侵袭和复制的能力对于确定预防膀胱侵袭和持久性的新疗法的靶点至关重要。 最近的数据表明，IBC的形成后的第一个24小时内实验性接种细菌到小鼠泌尿道构成了一个强大的人口瓶颈限制细菌多样性进展到感染的后期阶段。此外，在同一时间段内，诱导强烈的免疫应答使小鼠易于经历持续性菌尿和慢性膀胱炎。该提案探讨了以下假设：急性感染期间细胞内小生境的占据直接导致免疫反应，使宿主易患持续性菌尿和复发性/慢性膀胱炎。利用UTI的良好表征的鼠模型，将确定导致急性UTI期间显著瓶颈的分子机制、急性致病事件与长期UTI结果之间的直接关系以及顺序膀胱接种对感染的影响。本研究的目的是探讨急性UTI发病过程中影响感染结局的关键事件。这项研究的完成将有助于确定发病机制中的关键事件，可以用新的治疗方法来限制UTI的发病率。

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.