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

Hultgren SJ (2010) Early Severe Inflammatory Responses to Uropathogenic E. coli Predispose to Chronic and Recurrent Urinary Tract Infection. PLoS Pathog 6(8): e1001042. doi:10.1371/journal.ppat.1001042 Early Severe Inflammatory Responses to Uropathogenic E. coli Predispose to Chronic and Recurrent Urinary Tract Infection Thomas J. Hannan 0 Indira U. Mysorekar 0 Chia S. Hung 0 Megan L. Isaacson-Schmid 0 Scott J. 0 Craig R. Roy, Yale University School of Medicine, United States of America 0 1 Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine , St. Louis , Missouri, United States of America, 2 Department of Pathology and Immunology, Washington University School of Medicine , St. Louis , Missouri, United States of America, 3 Department of Obstetrics and Gynecology, Washington University School of Medicine , St. Louis, Missouri , United States of America 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 postinfection, 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. - Funding: This work was supported by National Institutes of Health Grant DK51406 and Office of Research on Womens Health Specialized Center of Research Grant DK64540 (SJH), a Mentored Clinical Scientist Research Career Development Award K08 AI083746 (TJH), and an individual National Research Service Award F32CA108328 and a Pathway to Independence Award K99/R00 DK080643 (IUM). The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant #P30 CA91842. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Persistent microbial infections are a rapidly expanding problem because of increased antimicrobial resistance [1]. This trend is particularly concerning because of the increasingly appreciated role that chronic infections may play in cancer and chronic inflammatory diseases [2,3,4]. One key example is that of urinary tract infections (UTI), which are common, highly recurrent, and can become chronic [5,6]. Females are disproportionately afflicted by UTI: 50% of all women will have an episode at some point in their lifetime, and 20 to 30% will have a recurrence within 3 to 4 months of the acute infection [7]. 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]. However, the molecular basis for rUTI and how this may relate to mechanisms of chronic infection, where adaptive immunity also falls short, are unknown. Furthermore, while antibiotic therapy has been resoundingly successful in treating acute UTI, recent increases in the prevalence of antibiotic-resistant uropathogenic strains in the community threaten to make chronic UTI common again [5,13,14]. Thus, understanding the host mechanisms contributing to chronic UTI, and other chronic bacterial infections of the mucosae, is of critical importance. Uropathogenic Escherichia coli (UPEC) are by far the most common cause of UTI, accounting for 80% of outpatient infections and 25% of nosocomial infections [15]. During an acute episode, UPEC adhere to and invade the superficial facet cells of the urinary mucosal epithelium (urothelium) in a type 1 pili-dependent manner [16,17]. UPEC invasion has been reported to involve several components of lipid rafts such as caveolin-1, an integral membrane protein found in the inner leaflet of the lipid 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 immunemediated 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. bilayer [18]; Rac1, a member of the Rho f (...truncated)