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.
Highlights
Persistent microbial infections are a rapidly expanding problem because of increased antimicrobial resistance [1]
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
We demonstrate that mice with a history of chronic bladder infection that was subsequently cleared with antibiotic treatment are highly susceptible to further urinary tract infections (UTI)
Summary
Persistent microbial infections are a rapidly expanding problem because of increased antimicrobial resistance [1]. The high incidence of recurrent UTI (rUTI) suggests that many individuals do not develop protective immunity to uropathogens, though the capacity to do so has been demonstrated in both murine and primate experimental model systems and a phase 2 clinical vaccine trial in women [8,9,10]. This failure of adaptive immunity may be partially explained by host genetic and environmental factors, such as a maternal history of UTI and childhood exposure to uropathogens, which appear to play significant roles in determining susceptibility to rUTI [11,12]. Understanding the host mechanisms contributing to chronic UTI, and other chronic bacterial infections of the mucosae, is of critical importance
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