Bacterial Invasion and Trafficking within the Bladder

膀胱内的细菌入侵和贩运

• 批准号: 8259743
• 负责人: MATTHEW A MULVEY
• 金额: $ 37.38万
• 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/8259743
• 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; public health relevance; 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. 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.

描述（由申请方提供）：尿路致病性大肠杆菌（UPEC）菌株是尿路感染（UTI）的主要病原体，尿路感染一直是最常见的感染性疾病之一。UPEC可以侵入宿主膀胱上皮细胞，随后繁殖，形成类似生物膜的大细胞内包涵体。或者，细胞内UPEC可以在更静止、非复制的状态下以低水平持续存在，这可能成为慢性和复发性急性尿路感染的储存库。越来越多的证据表明，在先天性和适应性宿主防御以及抗生素治疗的情况下，UPEC进入尿路内的宿主细胞和组织会促进细菌的持续存在。几乎所有的UPEC分离株编码丝状粘附细胞器称为1型皮利。我们已经发现，1型菌毛粘附素FimH可以从事主机1321整联蛋白受体在一个非经典的方式，从而激活信号级联，导致肌动蛋白依赖性内化的UPEC。我们的初步数据表明，FimH介导的宿主细胞的细菌入侵是依赖于肌动蛋白和微管细胞骨架网络之间的串扰，虽然这种串扰的性质仍然不确定。进入过程还需要来自网格蛋白和不同的网格蛋白相关衔接蛋白的输入。网格蛋白的最佳特征在于其在小分子如生长因子的摄取中的作用，但其促进更大颗粒如UPEC和其他侵入性病原体的内化的能力最近才被认识到，并且仍然知之甚少。本申请的主要目的是定义介导UPEC侵入膀胱上皮细胞的宿主因子，重点是微管-肌动蛋白串扰和网格蛋白的功能作用。还将评估宿主细胞侵袭对宿主内UPEC的建立和持续性的影响。希望这项工作能更全面地了解急性、复发性和慢性尿路感染的发病机制，最终促进治疗和预防这些异常常见感染的改进疗法的发展。 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。