Urothelial Epigenome Reprogramming by Uropathogenic E. coli Underlies Recurrent UTI Susceptibility

Bacterial urinary tract infections (UTIs) are extremely common worldwide with significant morbidity resulting from frequent recurrences (rUTIs). The biological mechanisms that determine susceptibility to rUTIs nevertheless remain enigmatic. Previous work with C3H/HeN mice infected with uropathogenic E. coli (UPEC) showed that this was an effective model system to recapitulate the two possible outcomes from an acute UTI in the absence of antibiotic therapy: self-resolution or chronic infection. This research suggested that differential remodeling of bladder tissue dependent on disease history determined the level of susceptibility to rUTIs.

In a new study, Russell et al. hypothesized that epigenetic alterations in urothelial stem cells (USCs) are key events in this bladder mucosal remodeling. To investigate this, primary USC lines were derived from mouse bladders with different disease histories and used to generate urothelium in vitro. Subsequent analysis revealed variations in chromatin accessibility, DNA methylation, and histone modifications in the USC lines that affected transcriptional expression involving caspase-1-mediated cell death and cyclooxygenase-2 (Cox-2)-regulated inflammatory responses, differentially impacting rUTI susceptibility (1). This intriguing research thus identifies epithelial-intrinsic remodeling and innate response training resulting from epi-mutagen (i.e., UPEC infection) reshaping of the urothelial epigenome. Future work will determine whether similar events occur with other types of infections or inflammatory diseases.

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