Journal
NATURE MICROBIOLOGY
Volume 2, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/nmicrobiol.2016.196
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Funding
- National Institutes of Health (NIH)
- Office of Research on Women's Health Specialized Center of Research [P50 DK64540, R01 DK51406, AI95542]
- Mucosal Immunology Studies Team consortium [U01 AI095776]
- Young Investigator
- Mentored Clinical Scientist Research Career Development Award [K08 AI083746, F30 DK096751]
- National Science Foundation [DGE-1143954]
- Rheumatic Disease Core Center at Washington University [P30-AR048335]
- NIAID [U19 AI110818]
- NIH NIDCD [P30DC04665]
- Washington University Center for Cellular Imaging (WUCCI)
- Washington University School of Medicine
- Children's Discovery Institute of Washington University and St Louis Children's Hospital
- Foundation for Barnes-Jewish Hospital
- National Institute for Neurological Disorders and Stroke [NS086741]
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Recurrent bacterial infections are a significant burden worldwide, and prior history of infection is often a significant risk factor for developing new infections. For urinary tract infection (UTI), a history of two or more episodes is an independent risk factor for acute infection. However, mechanistic knowledge of UTI pathogenesis has come almost exclusively from studies in naive mice. Here we show that, in mice, an initial Escherichia coli UTI, whether chronic or self-limiting, leaves a long-lasting molecular imprint on the bladder tissue that alters the pathophysiology of subsequent infections, affecting host susceptibility and disease outcome. In bladders of previously infected versus non-infected, antibiotic-treated mice, we found (1) an altered transcriptome and defects in cell maturation, (2) a remodelled epithelium that confers resistance to intracellular bacterial colonization, and (3) changes to cyclooxygenase-2-dependent inflammation. Furthermore, in mice with a history of chronic UTI, cyclooxygenase-2-dependent inflammation allowed a variety of clinical E. coli isolates to circumvent intracellular colonization resistance and cause severe recurrent UTI, which could be prevented by cyclooxygenase-2 inhibition or vaccination. This work provides mechanistic insight into how a history of infection can impact the risk for developing recurrent infection and has implications for the development of therapeutics for recurrent UTI.
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