Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection

Abstract

Purpose of review: Recurrent urinary tract infection (rUTI) is a serious clinical problem, yet effective therapeutic options are limited, especially against multidrug-resistant uropathogens. In this review, we explore the development of a clinically relevant model of rUTI in previously infected mice and review recent developments in bladder innate immunity that may affect susceptibility to rUTI.

Recent findings: Chronic bladder inflammation during prolonged bacterial cystitis in mice causes bladder mucosal remodelling that sensitizes the host to rUTI. Although constitutive defenses help prevent bacterial colonization of the urinary bladder, once infection occurs, induced cytokine and myeloid cell responses predominate and the balance of immune cell defense and bladder immunopathology is critical for determining disease outcome, in both naïve and experienced mice. In particular, the maintenance of the epithelial barrier appears to be essential for preventing severe infection.

Summary: The innate immune response plays a key role in determining susceptibility to rUTI. Future studies should be directed towards understanding how the innate immune response changes as a result of bladder mucosal remodelling in previously infected mice, and validating these findings in human clinical specimens. New therapeutics targeting the immune response should selectively target the induced innate responses that cause bladder immunopathology, while leaving protective defenses intact.

FIGURE 1

The innate immune response to acute UPEC cystitis. During acute UPEC infection of the urinary bladder, a series of coordinated and sequential host – pathogen interactions determine disease outcome. The circled numbers indicate a sequence of initial events during acute cystitis: ‘1’ indicates events that happen within the first 1 – 2 h of experimental colonization; ‘2’ indicates events that occur within the first 4 – 6 h of colonization; and ‘3’ indicates events that occur from 6 to 24 h postinfection. Responses discussed in this literature review are highlighted in red. BMP4, bone morphogenetic protein 4; G-CSF, granulocyte colony stimulating factor; IBC, intracellular bacterial community; IL-1, interleukin 1; MMP-9, matrix metallopeptidase 9; QIR, quiescent intracellular reservoir; PRR, pattern recognition receptor; TLR4, Toll-like receptor 4; TNFα, tumour necrosis factor alpha [ – 52,53^▪▪,54^▪,55^▪▪,56,57,58^▪,59^▪,60,61].

FIGURE 2

Model for susceptibility to acute, chronic and recurrent cystitis. We hypothesize that an acute host – pathogen checkpoint exists that determines disease outcome within the first 24 h of the acute infection. If the immune response is too limited, the host may fail to clear the infection and consequently will develop persistent bacteriuria and bladder infection that may be asymptomatic. In contrast, an immune response that is too severe may cause bladder immunopathology during acute cystitis that leads to the development of persistent bacteriuria and bladder infection that may be symptomatic. This is accompanied by bladder disease indicative of chronic cystitis, which, in mice, is accompanied by urothelial hyperplasia with a lack of terminal differentiation. Furthermore, evidence in mice suggests that a severe first-time infection that is left untreated for 2 weeks or more causes changes to the bladder mucosa that render it more sensitive to bacteria upon reinoculation. Figure adapted from [89].