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Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract

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  • Authors: Lori A. Birder1, David J. Klumpp2
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Departments of Medicine and Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; 2: Departments of Urology and Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60610; 3: University of Utah, Salt Lake City, UT; 4: University of Washington, Seattle, WA; 5: Northwestern University, Chicago, IL
  • Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.UTI-0023-2016
  • Received 07 April 2016 Accepted 18 April 2016 Published 23 September 2016
  • Lori A. Birder, lbirder@pitt.edu
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  • Abstract:

    Urinary tract infection (UTI) pathogenesis is understood increasingly at the level of the uropathogens and the cellular and molecular mediators of host inflammatory responses. However, little is known about the mediators of symptoms during UTI and what distinguishes symptomatic events from asymptomatic bacteriuria. Here, we review bladder physiology and sensory pathways in the context of an emerging literature from murine models dissecting the host and pathogen factors mediating pain responses during UTI. The bladder urothelium is considered a mediator of sensory responses and appears to play a role in UTI pain responses. Virulence factors of uropathogens induce urothelial damage that could trigger pain due to compromised bladder-barrier function. Instead, bacterial glycolipids are the major determinants of UTI pain independent of urothelial damage, and the O-antigen of lipopolysaccharide modulates pain responses. The extent of pain modulation by O-antigen can have profound effects, from abolishing pain responses to inducing chronic pain that results in central nervous system features reminiscent of neuropathic pain. Although these effects are largely dependent upon Toll-like receptors, pain is independent of inflammation. Surprisingly, some bacteria even possess analgesic properties, suggesting that bacteria exhibit a wide range of pain phenotypes in the bladder. In summary, UTI pain is a complex form of visceral pain that has significant potential to inform our understanding of bacterial pathogenesis and raises the specter of chronic pain resulting from transient infection, as well as novel approaches to treating pain.

  • Citation: Birder L, Klumpp D. 2016. Host Responses to Urinary Tract Infections and Emerging Therapeutics: Sensation and Pain within the Urinary Tract. Microbiol Spectrum 4(5):UTI-0023-2016. doi:10.1128/microbiolspec.UTI-0023-2016.

Key Concept Ranking

Type 1 Pili
0.5994598
Bacterial Pathogenesis
0.55353874
Urinary Tract Infections
0.47879922
Infectious Diseases
0.42197692
Microbial Pathogenesis
0.42197692
0.5994598

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/content/journal/microbiolspec/10.1128/microbiolspec.UTI-0023-2016
2016-09-23
2017-11-25

Abstract:

Urinary tract infection (UTI) pathogenesis is understood increasingly at the level of the uropathogens and the cellular and molecular mediators of host inflammatory responses. However, little is known about the mediators of symptoms during UTI and what distinguishes symptomatic events from asymptomatic bacteriuria. Here, we review bladder physiology and sensory pathways in the context of an emerging literature from murine models dissecting the host and pathogen factors mediating pain responses during UTI. The bladder urothelium is considered a mediator of sensory responses and appears to play a role in UTI pain responses. Virulence factors of uropathogens induce urothelial damage that could trigger pain due to compromised bladder-barrier function. Instead, bacterial glycolipids are the major determinants of UTI pain independent of urothelial damage, and the O-antigen of lipopolysaccharide modulates pain responses. The extent of pain modulation by O-antigen can have profound effects, from abolishing pain responses to inducing chronic pain that results in central nervous system features reminiscent of neuropathic pain. Although these effects are largely dependent upon Toll-like receptors, pain is independent of inflammation. Surprisingly, some bacteria even possess analgesic properties, suggesting that bacteria exhibit a wide range of pain phenotypes in the bladder. In summary, UTI pain is a complex form of visceral pain that has significant potential to inform our understanding of bacterial pathogenesis and raises the specter of chronic pain resulting from transient infection, as well as novel approaches to treating pain.

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Figures

Image of FIGURE 1
FIGURE 1

Opposing neural control during bladder filling and voiding. Circuits associated with filling (red) and voiding (green). During filling, receptor-mediated sensory signals from the bladder (blue arrow) are conveyed via the pelvic nerve, eliciting sphincter contraction and detrusor relaxation to retain urine. During voiding, sphincter relaxation and bladder contraction are achieved by inhibitory circuits that suppress the filling state and active circuits that promote detrusor contraction and thus urination ( 17 ).

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.UTI-0023-2016
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Image of FIGURE 2
FIGURE 2

Inflammatory pain. Factors within the inflammatory microenvironment can trigger pain responses. These factors may be released by damaged cells at the site of injury or by leukocytes. Such inflammatory mediators can trigger action potentials in sensory neurons or reduce firing thresholds for other environmental or physiologic stimuli.

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.UTI-0023-2016
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Image of FIGURE 3
FIGURE 3

UPEC induces pain separable from other facets of UTI pathogenesis. FimH acts as a tethered toxin that mediates urothelial apoptosis and consequent bladder-barrier dysfunction. LPS plays dual roles through its interactions with TLR4. In addition to the well-characterized role as a trigger for inflammation, LPS mediates pelvic-pain responses. Reproduced from ( 102 ), with permission.

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.UTI-0023-2016
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Image of FIGURE 4
FIGURE 4

LPS O-antigen acts as a rheostat to modulate UTI pain. Mice exhibited allodynia that varied with O-antigen. The acute-pain phenotype of UPEC strain NU14 was rendered chronic by deleting or the entire O-antigen gene cluster, but was suppressed by expressing 83972 O-antigen genes. K-12 strain SΦ874 induced chronic pain that was suppressed by expressing O-antigen O2a. Adapted from ( 96 ), with permission.

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.UTI-0023-2016
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Image of FIGURE 5
FIGURE 5

Chronic-pain pathway and ASB analgesia. A peripheral three-receptor cascade, consisting of TLR4, TRPV1, and CCR2, mediates development of chronic pain that is associated with central sensitization of the sacral spinal cord receiving bladder sensory input due to altered sensory input (green) or inhibitory control (red). Analgesic activity of ASB disrupts pain in the periphery and/or spinal cord.

Source: microbiolspec September 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.UTI-0023-2016
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