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Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity.
Biorxiv : the Preprint Server for Biology
|April 16, 2025
Summary
Tuberculosis severity varies, but animal models often fall short. This study identifies cathepsin Z (CTSZ) as a key factor influencing TB outcomes in mice and humans, highlighting a conserved CTSZ-CXCL1 pathway.
Area of Science:
- Genetics
- Immunology
- Pathogen Biology
Background:
- Tuberculosis (TB) presents diverse clinical outcomes, not fully replicated in current animal models.
- Genetic variation significantly impacts TB susceptibility and disease progression in humans.
- Previous work identified a TB susceptibility locus on mouse chromosome 2.
Purpose of the Study:
- To identify the specific gene underlying a previously mapped TB susceptibility locus.
- To investigate the role of cathepsin Z (CTSZ) in TB pathogenesis.
- To explore the conserved CTSZ-CXCL1 axis in TB severity across species.
Main Methods:
- Utilized the genetically diverse Collaborative Cross mouse panel for TB studies.
- Performed gene mapping to identify candidate genes.
- Generated Ctsz-ablated mice to assess functional impact.
- Analyzed cytokine production (CXCL1) in murine macrophages.
- Conducted a human household contact study in Uganda.
- Examined CTSZ localization in patient-derived TB granulomas.
Main Results:
- Identified cathepsin Z (Ctsz) as the lead candidate gene for TB susceptibility.
- Ctsz ablation in mice resulted in increased bacterial load, elevated CXCL1, and reduced survival.
- Disturbed Ctsz in murine macrophages enhanced CXCL1 production.
- Human CTSZ variants showed significant association with TB disease severity in a Ugandan cohort.
- CTSZ was localized to macrophages within human TB granulomas.
Conclusions:
- Cathepsin Z (CTSZ) plays a critical role in modulating TB disease severity.
- A conserved CTSZ-CXCL1 axis influences TB outcomes in both mice and humans.
- CTSZ is a potential therapeutic target for managing TB severity.
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