Plasma protein biomarkers predictive of progression to active tuberculosis among close contacts of patients with tuberculosis

A blood-based test capable of predicting progression to active tuberculosis (TB) before symptom onset could reduce numbers needed to treat and mitigate disease transmission. This study evaluated plasma protein as predictors of TB progression within a cohort of close contacts from a university TB outbreak. Plasma from 17 progressors who developed TB within 2 years, 28 interferon-gamma release assay (IGRA)-positive non-progressors, and 33 IGRA-negative healthy controls was profiled using the Olink proteomics platform. Progressors showed broad downregulation of proteins related to immune regulation, cell adhesion, and nucleotide metabolism, while no significant differences were observed between non-progressors and healthy controls. A six-protein panel comprising LRP11, REG4, FLT3LG, CCDC80, ADA, and DPP7 discriminated progressors from others with AUCs exceeding 0.85. Transcriptomic validation in two independent cohorts support consistent downregulation of these markers. These findings highlight a distinct protein signature with potential for risk differentiation of TB progression and inform the development of targeted preventive strategies.