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Virulence and Fitness Determinants of Uropathogenic

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  • Authors: Sargurunathan Subashchandrabose1, Harry L. T. Mobley2
  • Editors: Matthew A. Mulvey3, Ann E. Stapleton4, David J. Klumpp5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; 2: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; 3: University of Utah, Salt Lake City, UT; 4: University of Washington, Seattle, WA; 5: Northwestern University, Chicago, IL
  • Source: microbiolspec July 2015 vol. 3 no. 4 doi:10.1128/microbiolspec.UTI-0015-2012
  • Received 10 September 2012 Accepted 28 July 2014 Published 31 July 2015
  • Harry L.T. Mobley, hmobley@umich.edu
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  • Abstract:

    Urinary tract infection (UTI) caused by uropathogenic (UPEC) is a major global public health concern. Increasing antibiotic resistance found in clinical UPEC isolates underscores the immediate need for development of novel therapeutics against this pathogen. Better understanding of the fitness and virulence mechanisms that are integral to the pathogenesis of UTI will facilitate identification of novel strategies to prevent and treat infection with UPEC. Working towards that goal, the global UPEC research community has made great strides at unraveling various virulence and fitness genes. Here, we summarize major findings on virulence and fitness determinants that enable UPEC to successfully survive and colonize the urinary tract of mammalian hosts. Major sections of this chapter are devoted to the role of iron acquisition systems, metabolic pathways, fimbriae, flagella, toxins, biofilm formation, capsule, and strain-specific genes in the initiation and progression of UTIs. Transcriptomes of UPEC during experimental UTI in a murine model and naturally occurring UTI in women are compared to elucidate virulence mechanisms specifically involved in human UTI. Capitalizing on the advances in molecular pathogenesis research by translating these findings will help develop better clinical strategies for prevention and management of UTIs.

  • Citation: Subashchandrabose S, Mobley H. 2015. Virulence and Fitness Determinants of Uropathogenic . Microbiol Spectrum 3(4):UTI-0015-2012. doi:10.1128/microbiolspec.UTI-0015-2012.

Key Concept Ranking

PhoPQ Two-Component Regulatory System
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Gene Expression and Regulation
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/content/journal/microbiolspec/10.1128/microbiolspec.UTI-0015-2012
2015-07-31
2017-12-15

Abstract:

Urinary tract infection (UTI) caused by uropathogenic (UPEC) is a major global public health concern. Increasing antibiotic resistance found in clinical UPEC isolates underscores the immediate need for development of novel therapeutics against this pathogen. Better understanding of the fitness and virulence mechanisms that are integral to the pathogenesis of UTI will facilitate identification of novel strategies to prevent and treat infection with UPEC. Working towards that goal, the global UPEC research community has made great strides at unraveling various virulence and fitness genes. Here, we summarize major findings on virulence and fitness determinants that enable UPEC to successfully survive and colonize the urinary tract of mammalian hosts. Major sections of this chapter are devoted to the role of iron acquisition systems, metabolic pathways, fimbriae, flagella, toxins, biofilm formation, capsule, and strain-specific genes in the initiation and progression of UTIs. Transcriptomes of UPEC during experimental UTI in a murine model and naturally occurring UTI in women are compared to elucidate virulence mechanisms specifically involved in human UTI. Capitalizing on the advances in molecular pathogenesis research by translating these findings will help develop better clinical strategies for prevention and management of UTIs.

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Figures

Image of FIGURE 1
FIGURE 1

A simple model of iron uptake in UPEC. UPEC produces iron-scavenging molecules known as siderophores. Cognate outer-membrane receptors bind ferri-siderophore complexes or heme that are then imported into the periplasm. Within the periplasm, they associate with periplasmic-binding proteins. Translocation across the inner membrane involves ABC transporters. Iron is extracted from iron-siderophore complexes and heme via multiple reactions, denoted by broken arrows. In the presence of iron, Fur represses (X) transcription of the genes involved in iron uptake. Iron limitation within the host urinary tract results in the derepression of Fur-regulated genes, including siderophore-biosynthetic genes. UPEC, uropathogenic ; OM, outer membrane; P, periplasm; IM, inner membrane; C, cytoplasm; Fur, ferric-uptake regulator; Fe, ferric iron; and TonB, ExbB, ExbD, energy-transduction complex for transport of iron-containing complexes to the periplasm. doi:10.1128/microbiolspec.UTI-0015-2012.f1

Source: microbiolspec July 2015 vol. 3 no. 4 doi:10.1128/microbiolspec.UTI-0015-2012
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Image of FIGURE 2
FIGURE 2

Metabolism in UPEC during infection. Amino acids and di/oligo peptides are the primary sources of carbon and nitrogen for the UPEC within urinary tract. Mutants defective in peptide transport exhibit a fitness defect . Pyruvate is generated from amino acids and feeds into the citric-acid cycle and gluconeogenesis. Disruption of either citric-acid cycle or gluconeogenesis is detrimental for the survival of UPEC within the urinary tract. UPEC, uropathogenic ; OM, outer membrane; P, periplasm; IM, inner membrane; and C, cytoplasm. doi:10.1128/microbiolspec.UTI-0015-2012.f2

Source: microbiolspec July 2015 vol. 3 no. 4 doi:10.1128/microbiolspec.UTI-0015-2012
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Image of FIGURE 3
FIGURE 3

Regulation of flagellar motility in UPEC. , master regulator of the flagellar-biosynthesis cascade, is subject to both positive and negative regulation. Note that not all regulators affect the transcription of directly. Regulators such as PhoP and QseB are activated in response to specific cues encountered by UPEC. Various signals are integrated into the flagellar gene expression cascade via two-component regulatory systems and other signal-transduction cascades. UPEC, uropathogenic ; OM, outer membrane; P, periplasm; IM, inner membrane; and C, cytoplasm. doi:10.1128/microbiolspec.UTI-0015-2012.f3

Source: microbiolspec July 2015 vol. 3 no. 4 doi:10.1128/microbiolspec.UTI-0015-2012
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