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.

Summary The transitional epithelium of the bladder normally turns over slowly but, upon injury, undergoes rapid regeneration, fueled by basal uroepithelial stem and/or early progenitor cells (USCs). Little is known about the mechanisms underlying the injury response. Here, we investigate the mechanism of bladder epithelial regeneration in response to infection with uropathogenic E. coli (UPEC). We show that infection resulted in rapid sloughing of superficial cells, a marked inflammatory response, and a substantial spike in basal cell proliferation. Epithelial renewal following infectious injury was mediated in part by Bmp signaling. In mice with Cre-recombinase-mediated ablation of the Bmp4 receptor, Bmpr1a, infection leads to aberrant urothelial renewal resulting in a block in USC differentiation into superficial cells. The response to chemical injury with protamine sulfate (PS) also caused sloughing but no inflammation or USC activation. Together, our study indicates that UPEC infection activates the USC niche, and Bmp signaling is required for regulation of the USC response to infection.

Background Respiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. As azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in humans may provide a strategy for the prevention of post-bronchiolitis recurrent wheezing. Objectives To investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of post-bronchiolitis recurrent wheezing. Method A randomized, double-masked, placebo-controlled, proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks. Results Compared to placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (p=0.6), but resulted in a greater decline in nasal lavage IL-8 by day 15 (p=0.03). 22% of azithromycin-treated participants experienced at least 3 wheezing episodes compared to 50% of participants in the placebo group (p=0.07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (p=0.048), and in fewer days with respiratory symptoms over the subsequent year in comparison to placebo (36.7 vs. 70.1 days; p=0.01). Conclusion In this proof-of-concept study, azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to a third wheezing episode, and reduced overall respiratory morbidity over the subsequent year.