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

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.

Therapeutic effect of Dongbai-Tonglin-Fang, a Chinese herbal formula, on urinary tract infection in rat model

“…In addition, bacterial glycolipids are the major determinants of UTI pain independent of urothelial damage. In summary, UTI pain is a complex form of visceral pain, and its specific mechanism needs further investigation (Birder and Klumpp, 2016). Also, it was observed in this study that the DBTL can increase the latent period of foot licking induced by hot plate method and reduce the number of twisting induced by glacial acetic acid in mice, suggesting that DBTL displays an analgesic effect.…”

“…UTI also known as urinary system infection is the urinary tract epithelium inflammation caused by the invasion of bacteria. The pathogenesis of UTI is understood increasingly at the level of the uropathogens and the cellular and molecular mediators of host inflammatory responses (Bien et al, 2012;Birder and Klumpp, 2016). Women, children, and the elderly are highly predisposed to developing UTI (Foxman, 2014).…”

Bladder infection with uropathogenic Escherichia coli increases the excitability of afferent neurons

“…Although progress has been made in understanding the pathogenic mechanisms involved in the colonization of the urothelium by bacteria and the host immune response to UTI (for reviews, see Refs. 1,2,7,14,[84][85][86][87], the molecular mechanisms that mediate UTI-associated sensory symptoms remain largely unknown. The goals of this study were to gain understanding of the mechanism involved in the generation of irritative voiding symptoms and pain in a murine model of UTI and to define the contribution that bacterial factors have to these processes.…”

Role of neurogenic inflammation in local communication in the visceral mucosa

“…The urothelial cells are the first line of defense against pathogens. Studies using uropathogenic Escherichia coli (UPEC) infection of the bladder (chronic and acute) have shown apoptosis of the apical urothelial cell layer and inflammatory responses involving release of multiple mediators from the urothelium (such as interleukins and cytokines) [135], which result in structural damage to the urothelial barrier [136–138]. As a result urothelial cells start mounting multiple defense mechanisms to limit inflammatory responses [139].…”

“…It is believed that the acute pain is related to the release of mediators from the urothelium that produce inflammation and activation of afferent nerves. In addition, there is evidence for both inflammation dependent and independent pain mediated by endotoxin (a glycolipid on the outer membrane of Gram-negative bacteria) interacting with Toll-like receptors 4 [138, 142] and dependent on TRPA1 activation [143]. Chronic pain post UTI develops in some patients and it can also be reproduced in animal models.…”