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

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.

Fibrinolytic-deficiencies predispose hosts to septicemia from a catheter-associated UTI

“…IL-6 levels has been associated with severe and febrile uUTI 69 . However, during early, recurrent, or asymptomatic uUTI, IL-6 is repressed, unchanged or low levels 70 – 74 . In fact, TNFα is elevated during acute uUTI and is associated with recurrent uUTI 73 , 74 .…”

“…However, during early, recurrent, or asymptomatic uUTI, IL-6 is repressed, unchanged or low levels 70 – 74 . In fact, TNFα is elevated during acute uUTI and is associated with recurrent uUTI 73 , 74 . Importantly, TNFα is repressed during CAUTI (Fig.…”

It’s Time to Embrace Vaccination as We Enter the Postantibiotic Era of Recurrent Urinary Tract Infection Management

“…Our increasing understanding of urinary tract infectiondeg, understanding the epigenetic changes that occur in urothelial stem cells in the setting of acute UTI that may lead to the recurrent phenotype 10 ddovetail with rapid advances in new approaches to vaccine development spurred by the COVID-19 pandemic. While the future offers hope for even more effective immunomodulatory strategies for women with rUTI, we should embrace the innovation that current UTI vaccination approaches offer today.…”

Vaccination with Acinetobacter baumannii adhesin Abp2D provides protection against catheter-associated urinary tract infection

“…The lack of IgG titers suggests that factors other than adhesin-specific IgG, such as epithelial trained immunity or adaptive immunity to other bacterial epitopes, are likely responsible for the protective effect. [29][30][31][32][33] Immunization with A. baumannii Abp1/Abp2 adhesins provides protection from CAUTI. Mutations in abp1/abp2 attenuate virulence.…”