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Nat Microbiol DOI:10.1038/nmicrobiol.2016.196

A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease.

Publication TypeJournal Article
Year of Publication2016
AuthorsO'Brien, VP, Hannan, TJ, Yu, L, Livny, J, Roberson, EDO, Schwartz, DJ, Souza, S, Mendelsohn, CL, Colonna, M, Lewis, AL, Hultgren, SJ
JournalNat Microbiol
Date Published2016 Oct 31

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.


Alternate JournalNat Microbiol
PubMed ID27798558
PubMed Central IDPMC5308540
Grant ListF30 DK096751 / DK / NIDDK NIH HHS / United States
P30 DC004665 / DC / NIDCD NIH HHS / United States
P50 DK064540 / DK / NIDDK NIH HHS / United States
R01 DK051406 / DK / NIDDK NIH HHS / United States
P30 AR048335 / AR / NIAMS NIH HHS / United States
K08 AI083746 / AI / NIAID NIH HHS / United States
R24 NS086741 / NS / NINDS NIH HHS / United States
U19 AI110818 / AI / NIAID NIH HHS / United States
U01 AI095542 / AI / NIAID NIH HHS / United States
U01 AI095776 / AI / NIAID NIH HHS / United States