Year: 2025
Type: article
Abstract: Tuberculosis (TB) outcomes vary widely, from asymptomatic infection to mortality, yet most animal models do not recapitulate human phenotypic and genotypic variation. 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 (Ctsz) as a lead candidate underlying this TB susceptibility and show that Ctsz ablation leads to increased bacterial burden, pulmonary inflammation and decreased survival in mice. Ctsz 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 CTSZ 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-pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity.
Source: PLoS Biology
Authors: Rachel K. Meade, Oyindamola O. Adefisayo, Marco T. P. Gontijo, Summer J. Harris, Charlie J. Pyle, Kaley M. Wilburn, Alwyn M. V. Ecker, Erika J. Hughes, Paloma D. Garcia, Joshua Ivie, Michael L. McHenry, Penelope H. Benchek, Harriet Mayanja-Kizza, Jadee L. Neff, Dennis C. Ko, Jason E. Stout, Catherine M. Stein, Thomas R. Hawn, David M. Tobin, Clare M. Smith
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,500
Funders: Pew Charitable Trusts, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Case Western Reserve University, Fulbright Association, Steven G. Cancer Foundation, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, National Institutes of Health, Center for AIDS Research, Duke University, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Awards: G1000346655, G1156820657, G1174881085, G1486332044, G1487655884, G1903821366, G2791415992, Regional Biocontainment Laboratories Facility and Building System Upgrades Support, G3646433041, Biometric Genetic Analysis of CardiopulmonaryDisease, G4847828429, TUBERCULOSIS PREVENTION RESEARCH UNIT, G542087556, G6328186349, G6464348367, G6996199707, G7227357204, G7394684335, G8119251337, G8170994930, G8398698954, G8547379360, Linking Human TB Genetic Susceptibility Loci to Granuloma Biology, Center for AIDS Research, Cancer Center Support Grant (CCSG), G904109309
OpenAlex ID: W4414083630