Acute cystitis is rapidly becoming a therapeutic enigma, as antibiotic resistance is reducing the options to a minimum. Fortunately, new insights are now making it possible to explore immune response modifiers as alternatives to antibiotics. In patients with acute cystitis, infection triggers a rapid and potent inflammatory response in the bladder mucosa and clinical symptoms include pain, urgency and frequency of urination. The molecular basis of these symptoms is not well understood, but bacterial interactions with the bladder epithelium have been shown to create inflammatory cascades. This study examined how innate immune response genes influence the outcome of bladder infection and the pathogenesis of acute cystitis with a particular focus on IL-1β. C57BL/6 mice were intravesically infected with relevant uropathogenic Escherichia coli strain, CFT073. Acute cystitis in infected bladders was defined by macroscopic inspection of edema, hyperemia and purulent discharge followed by histology and immunohistochemistry, after 24 hours and seven days. Genetic determinants of transient bladder inflammation versus severe disease were subsequently identified using C57BL/6 mice with specific inflammasome gene deletions (Il1b-/-, Casp1-/-, Asc-/- and Nlrp3-/-). Using genome-wide transcriptomic analysis to characterize genes regulated by infection in the bladders of these mice, we identified acute cystitis as an IL-1β-driven, hyper-inflammatory disease. Consistent with such a role, Il1b-/- mice were protected from infection and pathology. In contrast Asc-/- and Nlrp3-/- mice developed progressive IL-1β-driven bladder inflammation and severe pathology, caused by a new, non-canonical IL-1β processing mechanism, involving the metalloproteinase MMP-7. Using IL-1β and MMP-7 as targets for immunotherapy, we succeeded in protecting susceptible Asc-/- mice against acute cystitis, confirming the potential of immunotherapy for this indication. The results reproduce important aspects of human cystitis in the murine urinary tract infection (UTI) model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common bacterial infections in man.
Overall design
Mouse were infected intravesically with E. coli CFT073 and bladder and kidney samples were collected after 7 days. Isolated RNA was subjected to Affymetrix whole genome transcriptomic analysis.
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