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

Worldwide, millions of people suffer from urinary tract infections (UTIs) every year with women accounting for the vast majority of cases. Uropathogenic Escherichia coli (UPEC) is the most common cause of infection and can provoke recurrent or chronic infections in 25% of women. To repel invading pathogens, the urinary tract mounts a vigorous innate immune response that includes the secretion of antimicrobial peptides (AMPs), in addition to rapid recruitment of phagocytes. Here, we investigate secretory leukocyte protease inhibitor (SLPI), an AMP with antiprotease, antimicrobial and immunomodulatory functions which is known to play protective roles at other mucosal sites but has not been well characterized in UTIs. Using a mouse model of UPEC-caused UTI, we show urine SLPI increases in infected C57BL/6J mice and that SLPI is localized and secreted from bladder epithelial cells. SLPI-deficient (Slpi-/-) mice undergoing UPEC-caused experimental UTI have higher urine bacterial titers, prolonged bladder inflammation, and elevated neutrophil elastase (NE) levels in their urine compared to wild-type (Slpi+/+) controls. Combined with bulk RNA sequencing of infected bladders, our data indicate that Slpi-/- mice have a dysregulated immune and tissue repair response after infection. We also measured SLPI in urine samples from a small group of female subjects 18-49 years old and show that the presence of a uropathogen is associated with increased urine SLPI whereas patients with a history of recent or recurrent UTI (rUTI) fail to increase SLPI in response to the presence of a uropathogen, suggesting dysregulation of SLPI expression in these women. Taken together, our findings show that SLPI protects against acute UTI in mice and provides preliminary evidence that SLPI is likewise regulated in response to uropathogen exposure in women.