What is it about?
Tuberculosis (TB) affects millions of people each year, but some become much sicker than others. We discovered that a single immune gene, called cathepsin Z, helps explain this difference. When this gene does not work properly, the body struggles to control infection and produces stronger inflammation. We found this pattern in mice and humans, showing that cathepsin Z plays a conserved role across species in shaping TB severity. Understanding how this gene affects the immune response could help identify people at higher risk and guide new strategies to reduce the damage caused by TB.
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Why is it important?
Genetic studies in African cohorts first linked the cathepsin Z gene to tuberculosis susceptibility more than 15 years ago, but its role in disease had never been tested experimentally. Using genetically diverse pre-clinical models, particularly mice, along with macaque and human data, we show that cathepsin Z directly influences the severity of TB. Our study provides the first experimental confirmation of a long-standing human genetic signal. By uncovering a shared pathway that connects host genetics, inflammation, and disease severity, our study demonstrates how pre-clinical mouse models can reveal the biological meaning behind genetic findings and guide future strategies to reduce severe TB.
Perspectives
From the perspective of the Smith Lab, this study represents a milestone in connecting genetic discoveries to experimental biology. For more than 15 years, cathepsin Z had been linked to tuberculosis susceptibility in African cohorts, yet its functional role remained unclear. By combining insights from human genetics, macaque studies, and pre-clinical mouse models, we were able to test and validate this long-standing association. It was particularly rewarding to see how genetically diverse mice could illuminate the mechanisms behind complex human disease outcomes. We hope this work inspires others to use diverse, integrative approaches to translate genetic signals into biological understanding, especially for diseases like TB that remain a major global health challenge.
Marco Tulio Pardini Gontijo
Duke University
Read the Original
This page is a summary of: Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity, PLoS Biology, September 2025, PLOS,
DOI: 10.1371/journal.pbio.3003377.
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