Subashchandrabose Sargurunathan, Hazen Tracy H, Brumbaugh Ariel R, Himpsl Stephanie D, Smith Sara N, Ernst Robert D, Rasko David A, Mobley Harry L T
Department of Microbiology and Immunology and.
Department of Microbiology and Immunology, Institute for Genome Sciences, School of Medicine, University of Maryland, Baltimore, MD 21201.
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18327-32. doi: 10.1073/pnas.1415959112. Epub 2014 Dec 8.
Uropathogenic Escherichia coli (UPEC) is the predominant etiological agent of uncomplicated urinary tract infection (UTI), manifested by inflammation of the urinary bladder, in humans and is a major global public health concern. Molecular pathogenesis of UPEC has been primarily examined using murine models of UTI. Translational research to develop novel therapeutics against this major pathogen, which is becoming increasingly antibiotic resistant, requires a thorough understanding of mechanisms involved in pathogenesis during human UTIs. Total RNA-sequencing (RNA-seq) and comparative transcriptional analysis of UTI samples to the UPEC isolates cultured in human urine and laboratory medium were used to identify novel fitness genes that were specifically expressed during human infection. Evidence for UPEC genes involved in ion transport, including copper efflux, nickel and potassium import systems, as key fitness factors in uropathogenesis were generated using an experimental model of UTI. Translational application of this study was investigated by targeting Cus, a bacterial copper efflux system. Copper supplementation in drinking water reduces E. coli colonization in the urinary bladder of mice. Additionally, our results suggest that anaerobic processes in UPEC are involved in promoting fitness during UTI in humans. In summary, RNA-seq was used to establish the transcriptional signature in UPEC during naturally occurring, community acquired UTI in women and multiple novel fitness genes used by UPEC during human infection were identified. The repertoire of UPEC genes involved in UTI presented here will facilitate further translational studies to develop innovative strategies against UTI caused by UPEC.
尿路致病性大肠杆菌（UPEC）是人类单纯性尿路感染（UTI）的主要病原体，表现为膀胱炎症，是全球主要的公共卫生问题。UPEC的分子发病机制主要通过UTI小鼠模型进行研究。针对这种主要病原体（其耐药性日益增强）开发新型疗法的转化研究，需要深入了解人类UTI发病过程中涉及的机制。对UTI样本与在人尿和实验室培养基中培养的UPEC分离株进行全RNA测序（RNA-seq）和比较转录分析，以鉴定在人类感染期间特异性表达的新适应性基因。利用UTI实验模型，获得了UPEC中参与离子转运的基因（包括铜外排、镍和钾导入系统）作为尿路发病机制中关键适应性因子的证据。通过靶向细菌铜外排系统Cus，对本研究的转化应用进行了研究。饮用水中补充铜可减少小鼠膀胱中大肠杆菌的定植。此外，我们的结果表明，UPEC中的厌氧过程参与促进人类UTI期间的适应性。总之，RNA-seq用于建立女性自然发生的社区获得性UTI期间UPEC的转录特征，并鉴定了UPEC在人类感染期间使用的多个新适应性基因。本文展示的参与UTI的UPEC基因库将有助于进一步开展转化研究，以制定针对UPEC引起的UTI的创新策略。
