The nature of immune responses to urinary tract infections

Key Points An overarching theme of the immune system in the bladder seems to be balancing the need to respond promptly to microbial challenge with the need to rapidly curtail inflammatory responses, as the structural integrity of the epithelial barrier is disrupted during prolonged immune responses. Bladder epithelial cells not only alert the immune system during infection but also directly mediate bacterial clearance by secreting antimicrobial compounds into the urine and by expelling invading bacteria back into the bladder lumen to reduce intracellular load. Crosstalk between different subsets of macrophages in the bladder coordinates the precise recruitment and onset of neutrophil responses, and thereby reduces harmful inflammatory reactions. Mast cells seem to have a dual role in immune regulation in the urinary tract. They promote early mobilization of immune cells into the bladder and are central to terminating these pro-inflammatory responses presumably when the bladder epithelial barrier is disrupted. However, this homeostatic action often results in blunted adaptive immune responses. Although neutrophils are the predominant immune cells mediating bacterial clearance in the bladder, excessive neutrophil responses can cause damage to the bladder tissue and predispose this organ to persistent infections. Several unconventional, but potentially effective, strategies have been described that can boost immune defences of the bladder to contain or prevent urinary tract infections. This Review describes our current understanding of innate and adaptive immune responses in the urinary tract and how immunomodulatory therapies could provide benefit in an era of increasing antibiotic resistance among uropathogens. The urinary tract is constantly exposed to microorganisms that inhabit the gastrointestinal tract, but generally the urinary tract resists infection by gut microorganisms. This resistance to infection is mainly ascribed to the versatility of the innate immune defences in the urinary tract, as the adaptive immune responses are limited particularly when only the lower urinary tract is infected. In recent years, as the strengths and weaknesses of the immune system of the urinary tract have emerged and as the virulence attributes of uropathogens are recognized, several potentially effective and unconventional strategies to contain or prevent urinary tract infections have emerged.