A rapid IL-9-secreting T cell response mediates uropathogenic Escherichia coli (UPEC) clearance in an acute UTI mouse model 2267492

Abstract

Abstract Introduction Urinary tract infections (UTIs) are commonly caused by gut-derived pathogenic bacteria, such as Escherichia coli, that infect the bladder. Antibiotic resistance in UTIs is of increasing clinical concern. IL-9 is a cytokine that regulates inflammation at mucosal barrier sites and promotes parasite clearance during helminth infection. Utilizing a uropathogenic E. coli (UPEC) mouse model, we examined IL-9 function in UTI progression, with a focus on epithelial integrity and bacterial clearance. Methods Public datasets and tissue biopsies obtained from the Cooperative Human Tissue Network were assessed for IL9R expression in patients with bacterial UTIs and healthy controls. For in vivo studies, WT, IL-9-deficient, IL-9R-deficient, and CD4-specific Il9 conditional mutant mice were transurethrally administered PBS with or without UPEC (strain UTI89). Mice were euthanized up to 24 hours post-inoculation for tissue processing; bladder bacterial burden, gene expression, immune infiltrate, and intracellular IL-9 protein levels were assessed. Results We found elevated IL-9 receptor expression on the luminal bladder surface in patients with bacterial UTIs compared to healthy controls. In the UPEC model, mice lacking IL-9 (Il9-/-) or its receptor (Il9r-/-) exhibited increased bacterial burden at 24 hours, reduced epithelial sloughing, and impaired immune recruitment, suggesting IL-9 supports rapid physical and immune-mediated bacterial clearance in UPEC infection. Using Il9 conditional mutant mice, we observed T cells as a source of IL-9. IL-9 secretion was detected from multiple T cell subsets, including CD4+ T cells, MAIT, and NKT cells, suggesting the potential involvement of innate T cell subsets. Conclusion T cell IL-9 is important for anti-bacterial immunity in the bladder. Ongoing studies will define the contributions of IL-9-producing T cell subsets in bacterial clearance and explore how these mechanisms may be therapeutically targeted for the treatment of antibiotic-resistant and recurring UTIs. Funding Source NIH NIAID (R01AI180518; R01AI057459; R21AI173929) Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)