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，占巨大的发病率和医疗费用。多达60%的妇女在其一生中会经历尿路感染，其中25%至40%的妇女经常复发，对抗生素治疗不耐受。超过80%的社区获得性尿路感染和50%的医院感染是由尿路致病性大肠杆菌（UPEC）引起的。尿路感染的发病机制是复杂的，upc能够在膀胱和肾脏内的多个生态位定植。UPEC利用被称为1型毛的表面表达的细胞外细胞器附着、侵入和复制终末分化的膀胱上皮表面突细胞。UPEC从内吞液泡中逃脱，在细胞质中复制成称为胞内细菌群落（IBCs）的大型生物膜样团块。在这种环境下，UPEC复制迅速，并受到先天免疫反应和排尿清除因素的保护。此外，IBCs内的upc对抗生素治疗具有耐药性，而抗生素治疗对肉汤培养中生长的生物体是有效的。在小鼠模型中，IBCs的形成对于细菌在膀胱中的定植至关重要，并且在复发性尿路感染的女性尿液中检测到IBCs。了解UPEC的发病机制及其侵袭和细胞内复制的能力，对于确定防止膀胱侵袭和持续的新治疗靶点至关重要。最近的数据表明，在实验性地将细菌接种到小鼠尿路后的最初24小时内，IBCs的形成构成了一个强大的种群瓶颈，限制了细菌多样性进展到感染的后期阶段。此外，在同一时间段内，诱导强大的免疫反应使小鼠容易经历持续性细菌尿和慢性膀胱炎。这一提议探讨了在急性感染期间占领细胞内生态位直接导致免疫反应的假设，使宿主易患持续性细菌尿和复发性/慢性膀胱炎。利用一个特征良好的尿路感染小鼠模型，将确定急性尿路感染期间显著瓶颈的分子机制，急性致病事件与长期尿路感染结局之间的直接关系，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尿路感染发病过程中影响感染结果的关键事件。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尿路感染的发病率。

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. PUBLIC HEALTH RELEVANCE: Urinary tract infections afflict millions of women with high rates of recurrence and substantial morbidity. The proposed research seeks to understand the mechanisms by which the most common cause uropathogenic E. coli avoids the immune system and persists in an inflamed urinary tract. The eventual goal is to create novel therapeutics targeting events during acute infection that will prevent bacterial persistence.