Chromatin Priming Index Reveals Compartmentalized Epigenetic Programming in Tuberculosis: A Computational Re-Analysis of Public Single-Cell Data

Background Tuberculosis treatment failure affects 5–10% of drug-susceptible patients, yet biomarkers predicting this outcome remain elusive. Single-cell multiomics data from TB patients offer an opportunity to explore epigenetic determinants of host-pathogen interactions. Methods We developed the Chromatin Priming Index (CPI), a computational metric quantifying the proportion of differentially expressed genes with accessible chromatin at their promoters. We re-analyzed published single-cell data from bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMC) of TB patients (GSE167232, GSE287288). Differential accessibility analysis compared BAL vs. PBMC cell populations. Results Our integrated dataset comprised 10,357 cells (5,412 BAL, 4,945 PBMC). Alveolar macrophages exhibited AP-1/NF-κB-dominated accessibility (CPI 77.6%) versus IRF/STAT signatures in blood monocytes (CPI 84.3%). Notably, Matrix Metalloproteinase genes (MMP1, MMP9) showed elevated chromatin accessibility in BAL macrophages despite low baseline expression, suggesting epigenetic 'priming' for tissue destruction. Literature review confirms MMP elevation correlates with cavitary disease and poor outcomes. Conclusions We introduce CPI as a novel epigenetic metric and identify MMP chromatin priming in lung macrophages as a hypothesis-generating biomarker candidate. Prospective studies with treatment outcome data are needed to validate the prognostic utility of this signature.