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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This work was supported by the National Institutes of Health (NIH) and the Office of Research on Women's Health Specialized Center of Research (P50 DK64540 and R01 DK51406 to S.J.H; AI95542 to S.J.H. and M.C.; Mucosal Immunology Studies Team consortium U01 AI095776 Young Investigator Award and Mentored Clinical Scientist Research Career Development Award K08 AI083746 to T.J.H. and F30 DK096751 to D.J.S.) and by the National Science Foundation (Graduate Research Fellowship DGE-1143954 to V.P.O.). RNA-seq analysis design and support was provided by the Rheumatic Disease Core Center at Washington University (P30-AR048335, to E.D.O.R). This publication was made possible by grant no. U19 AI110818 from NIAID. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. SEM studies and sample preparation were performed by the Research Center for Auditory and Vestibular Studies, which is supported by the NIH NIDCD grant P30DC04665, and by the Washington University Center for Cellular Imaging (WUCCI), which is supported by the Washington University School of Medicine, The Children's Discovery Institute of Washington University and St Louis Children's Hospital, the Foundation for Barnes-Jewish Hospital and the National Institute for Neurological Disorders and Stroke (NS086741). The authors thank K. Dodson and D.J. Frank for editorial assistance and D. Liu, J. Lett, M. Joens and J. Fitzpatrick for technical assistance.
S.J.H. may receive royalty income based on the FimH vaccine technology that he developed, which was licensed by Washington University to Sequoia Sciences. The other authors declare no competing financial interests.
Supplementary Figures 1–14, legends for Supplementary Tables 1–4 and Supplementary References (PDF 2163 kb)
Gene list from whole-bladder RNA-seq experiment, in which gene expression was compared between Sensitized and Resolved mice during convalescence (four weeks after the initiation of antibiotics). (XLSX 957 kb)
The fold changes in gene expression from whole-bladder RNA-seq, compared with the fold enrichment/depletion of the most significantly enriched/depleted proteins from a previously published analysis of the urothelial proteome enriched for membraneassociated glycoproteins. (XLSX 26 kb)
Pathway analysis showing the canonical pathways enriched in the differentially expressed genes in the RNA-seq experiment. (XLSX 30 kb)
Broad meta-pathways assembled by Ingenuity IPA from the specific enriched pathways given in Supplementary Table 3. (XLSX 34 kb)
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O'Brien, V., Hannan, T., Yu, L. et al. A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease. Nat Microbiol 2, 16196 (2017). https://doi.org/10.1038/nmicrobiol.2016.196
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