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The genetically diverse Collaborative Cross mouse panel models distinct facets of TB disease that occur in humans and allows identification of genomic loci underlying clinical outcomes. We previously mapped a TB susceptibility locus on mouse chromosome 2. Here, we identify cathepsin Z (\n                    <jats:italic>\n                      <jats:italic>Ctsz<\/jats:italic>\n                    <\/jats:italic>\n                    ) as a lead candidate underlying this TB susceptibility and show that\n                    <jats:italic>\n                      <jats:italic>Ctsz<\/jats:italic>\n                    <\/jats:italic>\n                    ablation leads to increased bacterial burden, pulmonary inflammation and decreased survival in mice.\n                    <jats:italic>\n                      <jats:italic>Ctsz<\/jats:italic>\n                    <\/jats:italic>\n                    disturbance within murine macrophages enhances production of chemokine (C-X-C motif) ligand 1 (CXCL1), a known biomarker of TB severity. From a Ugandan household contact study, we identify significant associations between\n                    <jats:italic>CTSZ<\/jats:italic>\n                    variants and TB disease severity. Finally, we examine patient-derived TB granulomas and report CTSZ localization within granuloma-associated macrophages, placing human CTSZ at the host\u2013pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003377","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T17:41:12Z","timestamp":1757439672000},"page":"e3003377","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity"],"prefix":"10.1371","volume":"23","author":[{"given":"Rachel K.","family":"Meade","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oyindamola O.","family":"Adefisayo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco T. 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