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Reaching the End of the Line: Urinary Tract Infections

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  • Authors: Kevin O. Tamadonfar1, Natalie S. Omattage2, Caitlin N. Spaulding3,4, Scott J. Hultgren5,6
  • Editors: Pascale Cossart7, Craig R. Roy8, Philippe Sansonetti9
    Affiliations: 1: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; 2: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; 3: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; 4: Harvard University School of Public Health, Boston, MA 02115; 5: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; 6: Center for Women’s Infectious Disease Research, Washington University, School of Medicine, St. Louis, MO 63110; 7: Institut Pasteur, Paris, France; 8: Yale University School of Medicine, New Haven, Connecticut; 9: Institut Pasteur, Paris, France
  • Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0014-2019
  • Received 31 July 2018 Accepted 01 April 2019 Published 07 June 2019
  • Scott J. Hultgren, [email protected]
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  • Abstract:

    Urinary tract infections (UTIs) cause a substantial health care burden. UTIs (i) are most often caused by uropathogenic (UPEC), (ii) primarily affect otherwise healthy females (50% of women will have a UTI), (iii) are associated with significant morbidity and economic impact, (iv) can become chronic, and (v) are highly recurrent. A history of UTI is a significant risk factor for a recurrent UTI (rUTI). In otherwise healthy women, an acute UTI leads to a 25 to 50% chance of rUTI within months of the initial infection. Interestingly, rUTIs are commonly caused by the same strain of that led to the initial infection, arguing that there exist host-associated reservoirs, like the gastrointestinal tract and underlying bladder tissue, that can seed rUTIs. Additionally, catheter-associated UTIs (CAUTI), caused by and as well as UPEC, represent a major health care concern. The host’s response of depositing fibrinogen at the site of infection has been found to be critical to establishing CAUTI. The Drug Resistance Index, an evaluation of antibiotic resistance, indicates that UTIs have become increasingly difficult to treat since the mid-2000s. Thus, UTIs are a “canary in the coal mine,” warning of the possibility of a return to the preantibiotic era, where some common infections are untreatable with available antibiotics. Numerous alternative strategies for both the prevention and treatment of UTIs are being pursued, with a focus on the development of vaccines and small-molecule inhibitors targeting virulence factors, in the hopes of reducing the burden of urogenital tract infections in an antibiotic-sparing manner.

  • Citation: Tamadonfar K, Omattage N, Spaulding C, Hultgren S. 2019. Reaching the End of the Line: Urinary Tract Infections. Microbiol Spectrum 7(3):BAI-0014-2019. doi:10.1128/microbiolspec.BAI-0014-2019.


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Urinary tract infections (UTIs) cause a substantial health care burden. UTIs (i) are most often caused by uropathogenic (UPEC), (ii) primarily affect otherwise healthy females (50% of women will have a UTI), (iii) are associated with significant morbidity and economic impact, (iv) can become chronic, and (v) are highly recurrent. A history of UTI is a significant risk factor for a recurrent UTI (rUTI). In otherwise healthy women, an acute UTI leads to a 25 to 50% chance of rUTI within months of the initial infection. Interestingly, rUTIs are commonly caused by the same strain of that led to the initial infection, arguing that there exist host-associated reservoirs, like the gastrointestinal tract and underlying bladder tissue, that can seed rUTIs. Additionally, catheter-associated UTIs (CAUTI), caused by and as well as UPEC, represent a major health care concern. The host’s response of depositing fibrinogen at the site of infection has been found to be critical to establishing CAUTI. The Drug Resistance Index, an evaluation of antibiotic resistance, indicates that UTIs have become increasingly difficult to treat since the mid-2000s. Thus, UTIs are a “canary in the coal mine,” warning of the possibility of a return to the preantibiotic era, where some common infections are untreatable with available antibiotics. Numerous alternative strategies for both the prevention and treatment of UTIs are being pursued, with a focus on the development of vaccines and small-molecule inhibitors targeting virulence factors, in the hopes of reducing the burden of urogenital tract infections in an antibiotic-sparing manner.

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Image of FIGURE 1

UPEC pathogenesis. (A) UPEC is housed in a reservoir in the gastrointestinal system. The bacteria are able to colonize the urinary tract from this reservoir. (B) Bacteria are able to adhere to and invade the bladder epithelial cells. (C) Bacterial cells can be evicted from the host cell in response. Bacterial cells can also enter the cytoplasm (D) and initiate IBC formation (E). (F) UPEC can, upon fluxing out of the host cells, filament and reinfect other urothelial cells. (G) To counteract intracellular pathogens, the host can initiate a program of host cell exfoliation. (H) Chronic cystitis in mice can occur with persistent high titers of bacteriuria. (I) QIRs can be established, in mice with resolved infections, in layers below superficial urothelial cells. Image and caption are adapted from reference 31 .

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0014-2019
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Image of FIGURE 2

Overview of UPEC fitness and virulence factors. Surface-associated structures that play a role in UTI pathogenesis include lipopolysaccharide, polysaccharide capsule, flagella, pili, toxins, secretion systems (SS), and siderophore receptors. Image and caption are adapted from reference 68 .

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0014-2019
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Image of FIGURE 3

Overview of CUP of pilus assembly and mode of action of antivirulence compounds. (A) Sec transports unfolded subunits of the pilus structure into the periplasmic space. (B, C, G, H) Pilus subunits interact with the pilus type-specific chaperone and fold. (D) Chaperone-subunit complexes interact with the N terminus of the pilus usher. (E) Secreted subunits, bound together through donor strand exchange, form the pilus. (F) Small-molecule inhibitors, mannosides and galactosides, antagonize interactions between the adhesive tip of the pilus and its ligand. Pilicides bind to the chaperone (I) and interrupt the interaction between chaperone and the N terminus of the usher (J). Image and caption are adapted from reference 31 .

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0014-2019
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Virulence factors in UPEC pathogenesis

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.BAI-0014-2019

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