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In examining alternative therapies, we previously found that the cysteine protease inhibitor E64 dramatically reduced bladder inflammation and bacterial dissemination in a murine model of\n                      <jats:italic toggle=\"yes\">E. faecalis<\/jats:italic>\n                      CAUTI. However, the role of cysteine proteases in pathogenesis and the target(s) of E64 are unknown. Here, we found that while it did not affect\n                      <jats:italic toggle=\"yes\">E. faecalis<\/jats:italic>\n                      growth\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , in a murine CAUTI model, E64 reduced host caspase-1-dependent cellular apoptosis and necrosis, levels of several pro-inflammatory cytokines, bladder epithelial damage, and formation of renal abscesses. Analysis of host cell transcription and inflammatory cell populations revealed that E64 did not affect neutrophil numbers but did enhance the expression of C-C chemokine receptor type 3 (CCR3), a receptor for eosinophil-specific chemokines, with a concomitant increase in eosinophil numbers. Treatments that reduced or increased the eosinophil response (anti-interleukin 5 antibody or eotaxin, respectively) confirmed a role for eosinophils in controlling bacterial burdens. Analysis of a panel of host cysteine proteases\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      demonstrated that E64 decreased the activation of cathepsin L; subsequently, we found that the infection of cathepsin L-deficient mice yielded lower catheter and bladder colonization compared to wild-type mice. In total, we have shown that host cysteine proteases exacerbate CAUTI pathogenesis, suggesting that cysteine protease modulation may represent a novel approach for the treatment of persistent CAUTI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Catheter-associated urinary tract infections (CAUTIs) are the most prevalent healthcare-associated infection globally, with\n                      <jats:italic toggle=\"yes\">Enterococcus faecalis<\/jats:italic>\n                      posing a significant threat due to widespread antibiotic resistance. This study identifies host cysteine proteases\u2014particularly cathepsin L and caspase-1\u2014as 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\n                      <jats:italic toggle=\"yes\">E. faecalis<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02161-25","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T12:00:32Z","timestamp":1758542432000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Host cysteine proteases promote the severity of catheter-associated urinary tract infection and kidney fibrosis"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4319-7432","authenticated-orcid":false,"given":"Wei","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine","place":["Saint Louis, USA"]},{"id":[{"id":"https:\/\/ror.org\/04jkbnw46","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Women\u2019s Infectious Disease Research, Washington University School of Medicine","place":["Saint Louis, USA"]},{"id":[{"id":"https:\/\/ror.org\/02erqft81","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical Sciences, Joan C. 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