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首页> 外文学位 >Uropathogenic Escherichia coli employ a conserved intracellular infection pathway that can be inhibited by novel anti-virulence therapeutics.
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Uropathogenic Escherichia coli employ a conserved intracellular infection pathway that can be inhibited by novel anti-virulence therapeutics.

机译：致病性大肠埃希氏菌采用保守的细胞内感染途径，该途径可被新型抗毒疗法抑制。

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摘要

Urinary tract infections (UTIs) affect 13 million women annually in the United States and are predominately caused by uropathogenic Escherichia coli (UPEC). In a murine cystitis model, UPEC utilize a multistep pathogenic pathway in which they invade and form intracellular bacterial communities (IBCs) within bladder facet cells. Type 1 pili expressing the adhesin, FimH, are necessary for UPEC binding and invasion of urothelial cells and formation of IBCs. UPEC ultimately disperse from the IBC, many with filamentous morphology, and infect other host urothelial cells. Using a panel of UPEC clinical isolates, this work evaluates the conservation of the IBC pathway across UPEC, the function of a UPEC pathogenicity island (PAI) in the UPEC pathway, and the therapeutic effect of inhibition of FimH.;Investigation of 18 clinical isolates revealed that the majority of isolates proceed through the IBC cascade confirming its relevance in UPEC infection. Due to the commonality of the UPEC pathway, this panel of clinical isolates was used to investigate other determinants important in UPEC infection. One potential virulence determinant is pUTI89, isolated from UTI89. pUTI89 has many characteristics of a PAI thus it was evaluated for its presence in UPEC isolates and its role in pathogenesis. Evidence of pUTI89 was found in 67% of UPEC isolates tested. Studies revealed that while there was no observable phenotype in vitro in the absence of pUTI89, there was a significant defect in binding, invasion and colonization at early time points post-infection, however, infection levels were restored by 24h post-infection. Since pUTI89 is not essential to UPEC infection, type 1 pili were used to develop a therapeutic against UPEC infection. Binding and invasion are critical to the UPEC pathway, thus inhibition of these early steps could result in unsuccessful colonization of the bladder. Knowledge of the FimH mannose-binding pocket enabled the rational development of mannosides that competitively inhibit binding to mannosylated uroplakins on the bladder surface.;These studies demonstrated the commonality of the IBC pathway among UPEC isolates as well as the importance of pUTI89 in early stages of UPEC infection. Knowledge of the UPEC pathway facilitated the development of novel therapeutics to inhibit binding and invasion and reduce infection.
机译：在美国，尿路感染（UTI）每年影响1300万妇女，并且主要由尿路致病性大肠杆菌（UPEC）引起。在鼠类膀胱炎模型中，UPEC利用多步致病途径，在其中侵入并在膀胱小平面细胞内形成细胞内细菌群落（IBC）。表达粘附素FimH的1型菌毛对于UPEC结合和侵袭尿道上皮细胞以及IBC的形成是必需的。 UPEC最终从IBC散布，许多呈丝状形态，并感染其他宿主尿道上皮细胞。这项工作使用一组UPEC临床分离株评估了跨UPEC的IBC途径的保守性，UPEC途径中UPEC致病岛（PAI）的功能以及抑制FimH的治疗效果。研究18种临床分离株揭示大多数分离株通过IBC级联进行，证实了其与UPEC感染的相关性。由于UPEC途径的共通性，该临床分离株用于研究对UPEC感染重要的其他决定因素。从UTI89分离的一种潜在的毒力决定因素是pUTI89。 pUTI89具有PAI的许多特征，因此对其在UPEC分离物中的存在及其在发病机理中的作用进行了评估。在67％的UPEC分离株中发现了pUTI89的证据。研究表明，尽管在没有pUTI89的情况下，在体外没有可观察到的表型，但在感染后的早期时间点，结合，侵袭和定植存在明显缺陷，但是感染后24h恢复了感染水平。由于pUTI89对UPEC感染不是必需的，因此使用1型菌毛来开发针对UPEC感染的治疗剂。结合和入侵对UPEC途径至关重要，因此抑制这些早期步骤可能会导致膀胱定植失败。对FimH甘露糖结合口袋的了解使甘露糖苷得以合理开发，从而竞争性抑制了与膀胱表面甘露糖基化尿激酶素的结合。;这些研究证明了UPEC分离物中IBC途径的共性以及pUTI89在早期阶段的重要性。 UPEC感染。 UPEC途径的知识促进了抑制结合和侵袭并减少感染的新型疗法的发展。

著录项

  • 作者

    Cusumano, Corinne Katherine.;

  • 作者单位

    Washington University in St. Louis.;

  • 授予单位 Washington University in St. Louis.;
  • 学科 Biology Microbiology.;Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 220 p.
  • 总页数 220
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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