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

Abstract

Urinary tract infections (UTIs) cause bladder hyperactivity and pelvic pain, but the underlying causes of these symptoms remain unknown. We investigated whether afferent sensitization contributes to the bladder overactivity and pain observed in mice suffering from experimentally induced bacterial cystitis. Inoculation of mouse bladders with the uropathogenic Escherichia coli strain UTI89 caused pelvic allodynia, increased voiding frequency, and prompted an acute inflammatory process marked by leukocytic infiltration and edema of the mucosa. Compared to controls, isolated bladder sensory neurons from UTI-treated mice exhibited a depolarized resting membrane potential, lower action potential threshold and rheobase, and increased firing in response to suprathreshold stimulation. To determine whether bacterial virulence factors can contribute to the sensitization of bladder afferents, neurons isolated from naïve mice were incubated with supernatants collected from bacterial cultures with or depleted of lipopolysaccharide (LPS). Supernatants containing LPS prompted the sensitization of bladder sensory neurons with both TTX-R and TTX-S action potentials. However, bladder sensory neurons with TTX-S action potentials were not affected by bacterial supernatants depleted of LPS. Unexpectedly, ultrapure LPS increased the excitability only of bladder sensory neurons with TTX-R action potentials, but the supplementation of supernatants depleted of LPS with ultrapure LPS resulted in the sensitization of both population of bladder sensory neurons. In summary, our studies indicate that multiple virulence factors released from UTI89 act on bladder sensory neurons to prompt their sensitization. These sensitized bladder sensory neurons mediate, at least in part, the bladder hyperactivity and pelvic pain seen in mice inoculated with UTI89.

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

“…It also plays a role in bacterial attachment to host cells and infections, notably in bladder infections caused by uropathogenic Escherichia coli [ 50 ]. Urinary tract infection (UTI) produced by uropathogenic E. coli (UPEC) promotes the sensitization of bladder afferent sensory neurons and the virulence factors produced by those bacteria contribute to the sensitization of bladder afferents in UTI [ 51 ]. The uroepithelial invasion by the bacteria occurs through lipid rafts, and Rac1 associated with caveolin-1 in those rafts is required for the bacterial invasion [ 52 ].…”

Urinary Tract Infection in Overactive Bladder: An Update on Pathophysiological Mechanisms

“…Furthermore, the toxins and metabolites released during bacterial growth and invasion are able to sensitise neurons, as well as in-directly activate neurons and evoke pain ( Chiu et al, 2013 ; Yang and Chiu, 2017 ; Blake et al, 2018 ; Uhlig et al, 2020 ). This has recently been explored in vitro using the cell bodies of bladder-innervating sensory neurons isolated from the dorsal root ganglia (DRG) of mice ( Montalbetti et al, 2022 ). In these experiments, both LPS and the virulence factors produced by UPEC during growth were able to sensitise subsets of bladder-innervating sensory neurons to enhance their excitability, representing an additional mechanism whereby infection may be able to evoke hypersensitive bladder symptoms.…”