Uropathogenic Escherichia coli infection-induced epithelial trained immunity impacts urinary tract disease outcome

Seongmi K. Russell, Jessica K. Harrison, Benjamin S. Olson, Hyung Joo Lee, Valerie P. O’Brien, Xiaoyun Xing, Jonathan Livny, Lu Yu, Elisha D.O. Roberson, Rajdeep Bomjan, Changxu Fan, Marina Sha, Shady Estfanous, Amal O. Amer, Marco Colonna, Thaddeus S. Stappenbeck, Ting Wang, Thomas J. Hannan, Scott J. Hultgren

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Previous urinary tract infections (UTIs) can predispose one to future infections; however, the underlying mechanisms affecting recurrence are poorly understood. We previously found that UTIs in mice cause differential bladder epithelial (urothelial) remodelling, depending on disease outcome, that impacts susceptibility to recurrent UTI. Here we compared urothelial stem cell (USC) lines isolated from mice with a history of either resolved or chronic uropathogenic Escherichia coli (UPEC) infection, elucidating evidence of molecular imprinting that involved epigenetic changes, including differences in chromatin accessibility, DNA methylation and histone modification. Epigenetic marks in USCs from chronically infected mice enhanced caspase-1-mediated cell death upon UPEC infection, promoting bacterial clearance. Increased Ptgs2os2 expression also occurred, potentially contributing to sustained cyclooxygenase-2 expression, bladder inflammation and mucosal wounding—responses associated with severe recurrent cystitis. Thus, UPEC infection acts as an epi-mutagen reprogramming the urothelial epigenome, leading to urothelial-intrinsic remodelling and training of the innate response to subsequent infection.

Original languageEnglish
Pages (from-to)875-888
Number of pages14
JournalNature microbiology
Volume8
Issue number5
DOIs
StatePublished - May 2023

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