Bacterial Invasion and Trafficking within the Bladder

描述（由申请人提供）：泌尿道通常是无菌环境，通过尿液的流动和无数的抗微生物分子和效应免疫细胞保持无微生物。然而，尽管这些强大的宿主防御和抗生素的使用越来越多，尿路感染（UTI）仍然是世界上最常见的传染病之一。尿路致病性大肠杆菌（UPEC）菌株是UTI的主要原因，其能够侵入宿主膀胱上皮细胞并随后繁殖，形成类似于生物膜的大的细胞内包涵体。或者，细胞内UPEC可以在更静止的非复制状态下以低水平持续存在，这可能成为未来复发性急性感染的储存库。尿路内宿主细胞和组织的侵入促进了UPEC在先天和适应性宿主反应以及许多抗生素治疗中的持续存在。本提案的主要目的是确定介导UPEC侵袭、细胞内生长和在膀胱上皮内持久存在的宿主和细菌因素。将采用生物化学、药理学、遗传学和显微镜方法与体内模型系统相结合。我们希望，拟议的工作将提供一个更完整的了解急性和复发性尿路感染的发病机制，并最终促进改进的治疗方法的发展，用于治疗和预防这些异常常见的感染。公共卫生相关性：尿路感染是最常见的传染病之一，在全世界造成严重的经济和医疗负担。通过描述尿路致病菌如何在宿主体内定植和持续存在，我们希望促进改进治疗方法的发展。

DESCRIPTION (provided by applicant): The urinary tract is normally a sterile environment, kept free of microbes by the flow of urine and by myriad anti-microbial molecules and effector immune cells. However, despite these formidable host defenses and the increasing usage of antibiotics, urinary tract infections (UTIs) remain among the most common of infectious diseases worldwide. Strains of uropathogenic Escherichia coli (UPEC), which are the principal cause of UTIs, are able to invade host bladder epithelial cells and subsequently multiply, forming large intracellular inclusions that resemble biofilms. Alternately, intracellular UPEC can persist at low levels in a more quiescent, non-replicating state that may serve as a reservoir for future recurrent acute infections. Invasion of host cells and tissues within the urinary tract promotes the persistence of UPEC in the face of both innate and adaptive host responses, as well as many antibiotic treatments. The primary objectives of this proposal are to define the host and bacterial factors that mediate UPEC invasion, intracellular growth, and persistence within the bladder epithelium. Biochemical, pharmacological, genetic, and microscopic approaches coupled with in vivo model systems will be employed. It is hoped that the proposed work will provide a more complete understanding of the pathogenesis of both acute and recurrent UTIs and ultimately facilitate the development of improved therapeutics for treating and preventing these exceptionally common infections. PUBLIC HEALTH RELEVANCE: Urinary tract infections are among the most common of infectious diseases, representing a serious economic and medical burden worldwide. By delineating how uropathogenic bacteria colonize and persist within the host, we hope to facilitate the development of improved therapeutics.