Host cysteine proteases promote the severity of catheter-associated urinary tract infection and kidney fibrosis

Catheter-associated urinary tract infections (CAUTIs) are the most prevalent healthcare-associated infection globally, with <i>Enterococcus faecalis</i> posing a significant threat due to widespread antibiotic resistance. This study identifies host cysteine proteases-particularly cathepsin L and caspase-1-as unrecognized drivers of CAUTI pathogenesis and renal fibrosis. Pharmacologic inhibition of these proteases using E64 reduces bladder inflammation, epithelial disruption, and kidney abscesses, while restoring fibrinogen and collagen homeostasis. Strikingly, E64 treatment unmasks a protective eosinophil response via CCR3 signaling that enhances bacterial clearance. Genetic deletion of cathepsin L recapitulates these protective effects, establishing it as a key host factor in <i>E. faecalis</i> persistence. These findings reveal host cysteine proteases as viable therapeutic targets for CAUTI and provide proof-of-concept for host-directed strategies that bypass antibiotic resistance.