Early Severe Inflammatory Responses to Uropathogenic E. coli Predispose to Chronic and Recurrent Urinary Tract Infection

Abstract

Chronic infections are an increasing problem due to the aging population and the increase in antibiotic resistant organisms. Therefore, understanding the host-pathogen interactions that result in chronic infection is of great importance. Here, we investigate the molecular basis of chronic bacterial cystitis. We establish that introduction of uropathogenic E. coli (UPEC) into the bladders of C3H mice results in two distinct disease outcomes: resolution of acute infection or development of chronic cystitis lasting months. The incidence of chronic cystitis is both host strain and infectious dose-dependent. Further, development of chronic cystitis is preceded by biomarkers of local and systemic acute inflammation at 24 hours post-infection, including severe pyuria and bladder inflammation with mucosal injury, and a distinct serum cytokine signature consisting of elevated IL-5, IL-6, G-CSF, and the IL-8 analog KC. Mice deficient in TLR4 signaling or lymphocytes lack these innate responses and are resistant, to varying degrees, to developing chronic cystitis. Treatment of C3H mice with the glucocorticoid anti-inflammatory drug dexamethasone prior to UPEC infection also suppresses the development of chronic cystitis. Finally, individuals with a history of chronic cystitis, lasting at least 14 days, are significantly more susceptible to redeveloping severe, chronic cystitis upon bacterial challenge. Thus, we have discovered that the development of chronic cystitis in C3H mice by UPEC is facilitated by severe acute inflammatory responses early in infection, which subsequently are predisposing to recurrent cystitis, an insidious problem in women. Overall, these results have significant implications for our understanding of how early host-pathogen interactions at the mucosal surface determines the fate of disease.

Author Summary

The natural history of urinary tract infection (UTI) with uropathogenic E. coli in humans frequently includes persistent bacterial shedding in the urine for weeks after the initial infection, despite varying degrees of improvement of symptoms. Although antibiotic treatment has been very successful in treating UTI, antibiotic resistance is rising and recurrent infections are a common and costly problem affecting millions of women. Here, we examine an experimental mouse model of chronic bladder infection with uropathogenic E. coli, the most common cause of UTI. We found that the development of chronic bladder infection was preceded by severe bladder tissue inflammation that results in injury to the lining of the bladder. Furthermore, immunodeficient mice that lacked these acute inflammatory responses were protected from chronic bladder infection, suggesting that the development of chronic bladder infection requires immune-mediated tissue damage during acute infection. Finally, we demonstrate that mice with a history of chronic bladder infection that was subsequently cleared with antibiotic treatment are highly susceptible to further UTI. Thus, this study has discovered possible overlap in the mechanisms underlying the development of chronic and recurrent UTI.