Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice

Abstract

Millions suffer from urinary tract infections (UTIs) worldwide every year with women accounting for the majority of cases. Uropathogenic Escherichia coli (UPEC) causes most of these primary infections and leads to 25% becoming recurrent or chronic. To repel invading pathogens, the urinary tract mounts a vigorous innate immune response that includes the secretion of antimicrobial peptides (AMPs), rapid recruitment of phagocytes and exfoliation of superficial umbrella cells. Here, we investigate secretory leukocyte protease inhibitor (SLPI), an AMP with antiprotease, antimicrobial and immunomodulatory functions, known to play protective roles at other mucosal sites, but not well characterized in UTIs. Using a mouse model of UPEC-caused UTI, we show that urine SLPI increases in infected mice and that SLPI is localized to bladder epithelial cells. UPEC infected SLPI-deficient (Slpi-/-) mice suffer from higher urine bacterial burdens, prolonged bladder inflammation, and elevated urine neutrophil elastase (NE) levels compared to wild-type (Slpi+/+) controls. Combined with bulk bladder RNA sequencing, our data indicate that Slpi-/-mice have a dysregulated immune and tissue repair response following UTI. We also measure SLPI in urine samples from a small group of female subjects 18-49 years old and find that SLPI tends to be higher in the presence of a uropathogen, except in patients with history of recent or recurrent UTI (rUTI), suggesting a dysregulation of SLPI expression in these women. Taken together, our findings show SLPI protects against acute UTI in mice and provides preliminary evidence that SLPI is likewise regulated in response to uropathogen exposure in women.

Single‐cell transcriptomics reveal the remodeling landscape of bladder in patients with obstruction‐induced detrusor underactivity

“…In the control group, the majority of the top 20 DEGs were associated with the epithelial cells, including epithelial barrier‐related genes (CLDN4, KRT19, and KRT18), and SLPI, a key gene reported to be localized to bladder epithelial cells and protect against urinary tract infection in mouse model. 15 Also, the GO enrichment analysis confirmed that the functions of such DEGs were related to the epithelial function (Figure 2B ). As for the BOO group, interestingly, the top two DEGs, SCGB3A1 and SCGB1A1, which belong to the secretoglobin family, have been reported to play a crucial role in immune regulation and could potentially serve as biomarkers for lung tissue damage caused by mechanical ventilation.…”

“…In the control group, the majority of the top 20 DEGs were associated with the epithelial cells, including epithelial barrier-related genes (CLDN4, KRT19, and KRT18), and SLPI, a key gene reported to be localized to bladder epithelial cells and protect against urinary tract infection in mouse model. 15 Also, the GO enrichment analysis confirmed that the functions of such DEGs were related to the epithelial function (Figure 2B). As for the BOO tissue.…”