Molecular determinants of pathogenesis and outcome in pulmonary and meningeal tuberculosis

Tuberculosis (TB) is a leading cause of death worldwide. Reducing TB burden and deaths is a global health priority, yet its immunopathogenesis remains poorly understood, hindering therapeutic advances. Uncontrolled Mycobacterium tuberculosis replication leads to dysregulated immune responses associated with poor treatment outcome. The overarching hypothesis addressed in this project is that genetic variations and cell types regulating immune responses determine TB pathogenesis and outcome, specifically of two novel genes Cornichon homolog 4 (CNIH4) and TraB Domain Containing 2A (TRABD2A). We will use pre-existing TB clinical cohorts and cellular models, integrating clinical metadata and multi-omics, to reveal and investigate new molecular determinants of TB pathogenesis and outcome. We will focus on pulmonary TB and TB meningitis. Our 6-year, 2-stage project has three aims: 1) Identify mechanisms that control pulmonary and cerebrospinal fluid bacterial burden before and during treatment, 2) Identify molecular determinants of death from TB meningitis, and 3) Understand how dexamethasone influences TB meningitis pathophysiology and survival. Elucidating the genetically-influenced cellular mechanisms of these determinants will transform understanding of TB pathogenesis, and identify new biomarkers and targets for host-directed therapy. Key words: tuberculosis, immune response, pathogenesis, treatment outcomes.