Host-specific induction of Escherichia coli fitness genes during human urinary tract infection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (51), p.18327-18332
• Main Authors: Subashchandrabose, Sargurunathan, Hazen, Tracy H., Brumbaugh, Ariel R., Hirnpsl, Stephanie D., Smith, Sara N., Ernst, Robert D., Rasko, David A., Mobley, Harry L. T.
• Format: Article
• Language: English
• Subjects: Biological Sciences; Comparative analysis; Copper; E coli; Escherichia coli; Escherichia coli - genetics; Escherichia coli - physiology; Gene Expression Regulation, Bacterial; Genes; Genes, Bacterial; Genomes; Humans; Infections; Pathogenesis; Ribonucleic acid; RNA; Urinary bladder; Urinary tract diseases; Urinary tract infections; Urinary Tract Infections - immunology; Urinary Tract Infections - microbiology; Urine; Uropathogenic Escherichia coli
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1415959112

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. Significance Escherichia coli is the most common cause of urinary tract infections (UTI) in humans. This bacterium is a major global public health concern because it is becoming resistant to currently available antibiotics. Therefore, it is imperative to develop new treatment and prevention strategies against this bacterium. However, the processes that promote survival of this bacterium within the human urinary tract during UTI are not clearly understood. Here we identify E. coli genes that promote survival within the urinary tract during naturally occurring UTI in women. Genes identified in this study represent targets for development of new therapies against UTI caused by E. coli .