TY - JOUR
T1 - Uropathogenic Escherichia coli infection-induced epithelial trained immunity impacts urinary tract disease outcome
AU - Russell, Seongmi K.
AU - Harrison, Jessica K.
AU - Olson, Benjamin S.
AU - Lee, Hyung Joo
AU - O’Brien, Valerie P.
AU - Xing, Xiaoyun
AU - Livny, Jonathan
AU - Yu, Lu
AU - Roberson, Elisha D.O.
AU - Bomjan, Rajdeep
AU - Fan, Changxu
AU - Sha, Marina
AU - Estfanous, Shady
AU - Amer, Amal O.
AU - Colonna, Marco
AU - Stappenbeck, Thaddeus S.
AU - Wang, Ting
AU - Hannan, Thomas J.
AU - Hultgren, Scott J.
N1 - Funding Information:
We thank 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 (CDI-CORE-2015-505), and the Foundation for Barnes-Jewish Hospital (3770), for preparing and imaging scanning electron microscopy samples. We thank M. Shih for developing Fiji ImageJ macro code for automatic cell size measurement of confocal images and K. Dodson for editorial assistance. This work was supported by the National Institutes of Health (U01 AI095542 to S.J.H. and M.C.; U19AI110818 to J.L.); a National Institutes of Health Mucosal Immunology Studies Team consortium Young Investigator Award (U01 AI095776 to T.J.H.); the Washington University Rheumatic Diseases Research Resource-based Center (P30 AR073752, E.D.O.R.); a McDonnell International Scholars Academy Fellowship at Washington University in St Louis (to S.K.R.); and a National Science Foundation Graduate Research Fellowship (#DGE –114395 to V.P.O.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85152448084&partnerID=8YFLogxK
U2 - 10.1038/s41564-023-01346-6
DO - 10.1038/s41564-023-01346-6
M3 - Article
C2 - 37037942
AN - SCOPUS:85152448084
SN - 2058-5276
VL - 8
SP - 875
EP - 888
JO - Nature microbiology
JF - Nature microbiology
IS - 5
ER -