Research Projects

Central Nervous System Tuberculosis (CNS-TB) is one of the deadliest forms of TB, disproportionately affecting young children and immunocompromised individuals (Rock et al., 2008). Though only 5% of extrapulmonary TB cases, CNS-TB causes ~100,000 cases annually, killing 1/3 of patients and leaving most survivors with irreversible neurological damage (Boubour et al., 2020). In 2024, 164,000 adults developed TB meningitis, with 78,200 deaths (Fang et al., 2024). Diagnosis remains difficult due to non-specific symptoms, poor sensitivity of routine tests, and limited access to brain tissue (Foppiano Palacios & Saleeb, 2020). While new tools like IRISA-TB show promise, they are not yet widely available (Meldau et al., 2019). There is a pressing need for better models and biomarkers to aid diagnosis, therapy, and understanding of CNS-TB. This project hypothesizes that Sonic Hedgehog (SHH) signaling modulates blood-brain barrier (BBB) integrity and inflammation in CNS-TB, and that molecular indicators like MMP-9, GFAP, and SHH-pathway proteins may serve as useful biomarkers. SHH signaling promotes BBB stability and limits inflammation, whereas matrix metalloproteinases disrupt the BBB (Brilha et al., 2017). We previously developed a murine CNS-TB model using Cyclopamine (a SHH inhibitor), which replicates key pathological features within 28 days (Mubarak et al., 2024). This study will investigate disease progression, BBB dysfunction, neuroinflammation, and pathology to identify biomarkers. Mice will be infected with M. tuberculosis H37Rv and treated with Purmorphamine, Cyclopamine, or standard therapy. Brains and CSF will be analyzed at days 2, 14, and 28 post-infection. The key objectives are: 1) to assess SHH pathway influence on BBB integrity and CNS-TB pathology; 2) to identify and validate time-linked biomarkers in brain, CSF, and serum, correlating them with bacterial load and inflammation; and 3) to evaluate these markers in clinical CSF/blood samples from patients. Core methods include histology, IHC, ELISA, multiplex assays, and ROC-based clinical validation. This study aims to establish a refined CNS-TB mouse model, uncover novel diagnostic biomarkers, and clarify the SHH pathway’s role in CNS-TB. The work has potential to improve diagnostics, guide therapy, and support translational research in TB neurobiology.