Abstract

Urinary tract infections (UTIs) afflict over 9 million women in America every year, often necessitating long-term prophylactic antibiotics. One risk factor for UTI is frequent sexual intercourse, which dramatically increases the risk of UTI. The mechanism behind this increased risk is unknown; however, bacteriuria increases immediately after sexual intercourse episodes, suggesting that physical manipulation introduces periurethral flora into the urinary tract. In this paper, we investigated whether superinfection (repeat introduction of bacteria) resulted in increased risk of severe UTI, manifesting as persistent bacteriuria, high titer bladder bacterial burdens and chronic inflammation, an outcome referred to as chronic cystitis. Chronic cystitis represents unchecked luminal bacterial replication and is defined histologically by urothelial hyperplasia and submucosal lymphoid aggregates, a histological pattern similar to that seen in humans suffering chronic UTI. C57BL/6J mice are resistant to chronic cystitis after a single infection; however, they developed persistent bacteriuria and chronic cystitis when superinfected 24 hours apart. Elevated levels of interleukin-6 (IL-6), keratinocyte cytokine (KC/CXCL1), and granulocyte colony-stimulating factor (G-CSF) in the serum of C57BL/6J mice prior to the second infection predicted the development of chronic cystitis. These same cytokines have been found to precede chronic cystitis in singly infected C3H/HeN mice. Furthermore, inoculating C3H/HeN mice twice within a six-hour period doubled the proportion of mice that developed chronic cystitis. Intracellular bacterial replication, regulated hemolysin (HlyA) expression, and caspase 1/11 activation were essential for this increase. Microarrays conducted at four weeks post inoculation in both mouse strains revealed upregulation of IL-1 and antimicrobial peptides during chronic cystitis. These data suggest a mechanism by which caspase-1/11 activation and IL-1 secretion could predispose certain women to recurrent UTI after frequent intercourse, a predisposition predictable by several serum biomarkers in two murine models.

Highlights

  • Nine million people present each year to primary care physicians with a urinary tract infection (UTI), costing nearly $2 billion yearly [1,2]

  • 1.5 million women are referred to urology clinics suffering from chronic recurrent UTI on a yearly basis necessitating the use of prophylactic antibiotics

  • Frequent and recent sexual intercourse correlates with the development of UTI, a phenomenon referred to clinically as ‘‘honeymoon cystitis.’’ Here, using superinfection mouse models, we identified bacterial and host factors that influence the likelihood of developing chronic UTI

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Summary

Introduction

Nine million people present each year to primary care physicians with a urinary tract infection (UTI), costing nearly $2 billion yearly [1,2]. 25–40% of these women will suffer recurrent UTI (rUTI), with 1.5 million women referred to urology clinics and often requiring prophylactic antibiotics to prevent recurrence [4,5,6]. In the absence of antibiotic therapy, up to 60% of women experience symptoms and/or bacteriuria lasting months after initial infection [9,10,11,12], implying that cystitis is not always self-limiting. If the infection persists without adequate treatment, the organisms have the capacity to ascend the ureters, causing pyelonephritis and sepsis [13]. Antibiotic resistant organisms further complicate infection and threaten to increase the likelihood of chronic UTI, pyelonephritis and potentially bacteremia [14,15]. It is imperative to understand the molecular mechanisms that underlie this problematic disease in order to develop novel therapies

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