Urinary tract infection (UTI) is a pervasive disease across all age groups. The presence of neutrophils in urine (pyuria) is a hallmark of UTI, yet neutrophil activation, function, and efficacy in controlling bacteria in urine is undefined. Recently, we found that Tamm-Horsfall protein (THP), the most abundant protein in human urine, binds an inhibitory sialic acid receptor on neutrophils. We hypothesized that THP is a critical host defense component against UTI through modulation of neutrophil responses. We coupled in vitro assays with purified human neutrophils, murine UTI models with wildtype (WT) and THP-deficient mice, pathology scoring, proteomics, flow cytometry, and glycan analyses to investigate the impact of THP on neutrophil function and host protection against uropathogen E. coli (UPEC). THP-deficient mice had increased bacterial burdens, neutrophil recruitment, and histopathological scoring compared to WT mice. We found that THP enhanced formation of neutrophil extracellular traps, also known as NETosis, both in human and mouse neutrophils ex vivo in a manner dependent on both THP and reactive oxygen species. We conclude that THP is a critical regulator for neutrophil NETosis in the urinary tract and that NETosis is a key host defense against UTI. THP may be a promising therapeutic target to improve UTI outcomes in susceptible populations.

Invited by Molly Ingersoll.