Peripheral blood transcriptomic reanalysis prioritizes a neutrophil– matrix metalloproteinase axis and doxycycline in adult tuberculous meningitis

<title>Abstract</title> <p> <bold>Objective</bold> To extend the publicly available adult tuberculous meningitis (TBM) transcriptomic resource of Hai et al. by testing whether a same-run whole-blood comparison can prioritize a coherent, experimentally testable host-directed therapy hypothesis. <bold>Results</bold> Among 207 HIV-negative adults with TBM and 295 adults with pulmonary tuberculosis (PTB), the TBM-versus-PTB contrast identified 53 differentially expressed genes. Neutrophil degranulation was the leading positive pathway (normalized enrichment score 3.3315; adjusted P = 6.84 × 10⁻³⁷), and MMP9 ranked first by maximal clique centrality. Two deconvolution methods supported higher neutrophil signals, with the MCP-counter neutrophil score correlating with MMP9 (Spearman ρ = 0.79). A broad blood signature transported to two active-TB cohorts (AUC 0.9408 and 0.9947), although active-TB-versus-sarcoidosis separation was modest (AUC 0.604). Mechanism auditing distinguished a direct curated doxycycline–MMP8 relation from a literature- and pose-supported MMP9 hypothesis. In the MMP9 protocol qualified by NFH self-redocking (RMSD 1.20 Å), doxycycline produced a zinc-proximal pose. These convergent findings prioritize broad MMP modulation with doxycycline for TBM-focused experimental testing. </p>