Bacterial Invasion and Trafficking within the Bladder

膀胱内的细菌入侵和贩运

• 批准号: 8660604
• 负责人: MATTHEW A MULVEY
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660604
• 关键词: Actins; Acute; Adaptor Signaling Protein; Adhesives; Affect; Antibiotic Therapy; Bacteria; Bacterial Adhesins; Binding; Biological Assay; Biological Models; Bladder; Cell Culture Techniques; Cells; Chronic; Clathrin; Clathrin Adaptors; Co-Immunoprecipitations; Communicable Diseases; Complex; DNA Sequence Rearrangement; Data; Development; Epithelial Cells; Event; Family member; Gene Silencing; Growth Factor; Host Defense; Infection; Integration Host Factors; Integrins; Invaded; Kinesin; Knockout Mice; Life; Link; Mediating; Medical Economics; Microbial Biofilms; Microtubules; Motor; Mus; Nature; Organelles; Pathogenesis; Pilum; Process; Proteomics; Recurrence; Research; Rho-associated kinase; Role; Signal Transduction; Site; Testing; Therapeutic; Tissues; Urinary tract; Urinary tract infection; Uropathogenic E. coli; Work; base; cellular imaging; defined contribution; improved; in vivo; inhibitor/antagonist; insight; particle; pathogen; prevent; receptor; rho GTP-Binding Proteins; small molecule; trafficking; uptake

DESCRIPTION (provided by applicant): Strains of uropathogenic Escherichia coli (UPEC) are the principal causative agents of urinary tract infections (UTIs), which continuously rank among the most common of infectious diseases. UPEC can 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 chronic and recurrent acute UTIs. Mounting evidence indicates that UPEC entry into host cells and tissues within the urinary tract promotes bacterial persistence in the face of both innate and adaptive host defenses, as well as antibiotic treatments. Virtually all UPEC isolates encode filamentous adhesive organelles called type 1 pili. We have found that the type 1 pilus adhesin FimH can engage host 1321 integrin receptors in a non-canonical fashion and thereby activate signaling cascades that result in the actin-dependent internalization of UPEC. Our preliminary data indicate that FimH-mediated bacterial invasion of host cells is dependent upon crosstalk between the actin and microtubule cytoskeletal networks, although the nature of this crosstalk remains undefined. The entry process also requires input from clathrin and distinct clathrin-associated adaptor proteins. Clathrin is best characterized for its role in the uptake of small molecules such as growth factors, but its ability to promote internalization of much larger particles like UPEC and other invasive pathogens has only recently been appreciated and remains poorly understood. The primary objectives of this application are to define the host factors that mediate UPEC invasion of bladder epithelial cells, with a focus on the functional roles of microtubule-actin crosstalk and clathrin. The impact that host cell invasion has on the establishment and persistence of UPEC within the host will also be assessed. It is hoped that the proposed work will provide a more complete understanding of the pathogenesis of acute, recurrent, and chronic UTIs, ultimately facilitating the development of improved therapeutics for treating and preventing these exceptionally common infections.

描述（由申请人提供）：尿道病大肠杆菌（UPEC）的菌株是尿路感染（UTI）的主要病因（UTI），它不断排名最常见的感染性疾病。 UPEC可以侵入宿主膀胱上皮细胞，然后随后繁殖，形成与生物膜相似的大细胞内夹杂物。或者，细胞内UPEC可以在更静止的，非复制状态下持续持续，该状态可以用作慢性和复发性急性尿道的储藏。越来越多的证据表明，UPEC进入尿路内的宿主细胞和组织可在面对先天和适应性宿主防御剂以及抗生素处理的情况下促进细菌持久性。实际上，所有UPEC分离株编码称为1 pili的丝状粘合剂细胞器。我们发现，1型Pilus粘附蛋白FIMH可以以非典型的方式吸引宿主1321整合素受体，从而激活信号级联，从而导致UPEC依赖肌动蛋白的内在化。我们的初步数据表明，FIMH介导的宿主细胞细菌侵袭取决于肌动蛋白和微管细胞骨架网络之间的串扰，尽管该串扰的性质仍然不确定。进入过程还需要网格蛋白和不同网格蛋白相关的衔接蛋白的输入。网格蛋白最能以其在摄取小分子（例如生长因子）中的作用来表征，但是它促进诸如UPEC和其他侵入性病原体（例如最近的较大颗粒）内在化的能力直到最近才得到欣赏，并且仍然知之甚少。该应用的主要目标是定义介导膀胱上皮细胞UPEC侵袭的宿主因子，重点是微管 - 肌动蛋白串扰和网格蛋白的功能作用。还将评估宿主细胞入侵对UPEC在宿主内的建立和持久性的影响。希望拟议的工作将对急性，经常性和慢性UTI的发病机理提供更完整的了解，最终促进改善治疗和防止这些异常常见感染的治疗疗法的发展。