Bladder mucosal afferents detect UTI and aid pathogen clearance

The bladder is innervated by a complex network of sensory neurons that detect and transmit mechanical and chemical signals to the central nervous system, regulating both urine storage and voiding, and mediating sensations of bladder fullness and pain. While stretch-sensitive afferents within the bladder wall are known to monitor bladder tension, the contribution of stretch-insensitive afferents that reside within the bladder mucosa to bladder sensation and function remains unclear. Here, we establish a mouse model of selective bladder mucosal afferent denervation using intravesical instillation of resiniferatoxin to define the functional roles of these fibers in health and disease. We assessed the impact of mucosal denervation on sensory nerve activity and bladder function in healthy mice and in a model of urinary tract infection (UTI) induced by acute bacterial challenge with uropathogenic Escherichia coli. We show that mucosa-innervating afferents do not influence bladder distension responses or voiding function under healthy conditions. In contrast, during UTI, these afferents become hypersensitive and serve as important drivers of infection-induced pelvic pain and urinary frequency, responses that contribute to bacterial clearance. Together, these findings identify bladder mucosal afferents as key sensors of pathogenic challenge and reveal a previously unrecognized mechanism that drives behavioral responses to reduce the burden and extent of UTI.