Host-directed nanotherapy for the treatment and imaging of tuberculous meningitis.

Abstract

RATIONALE: Tuberculous meningitis (TB meningitis) is a devastating infection where the host immune response drives brain injury. Standard adjunctive corticosteroids often fail to prevent neurological sequelae or improve survival in many populations. Host-directed therapies that can cross the blood-brain barrier (BBB) and reduce neuroinflammation are urgently needed. We evaluated a hydroxyl-terminated polyamidoamine (PAMAM) dendrimer as a theranostic nanoplatform to visualize and treat microglia-mediated neuroinflammation in a young rabbit model of TB meningitis. METHODS: A novel radiolabeled dendrimer (I-dendrimer) was synthesized for noninvasive positron emission tomography (PET) imaging, with post-mortem gamma counting and fluorescent-labeled dendrimer (D-Cy5) confirming biodistribution. For therapy, rabbits with TB meningitis (i.e., infected) received weekly intravenous dendrimer--acetyl cysteine (D-NAC) or phosphate buffered saline (PBS). After two weeks, treatment efficacy was evaluated with longitudinal neurobehavioral scores and multimodal PET (F-FDG for glucose metabolism,F-py-albumin for BBB integrity, andI-DPA-713 for microglial/macrophage activation). Post-mortem analyses included bacterial burden (colony-forming units [CFU]), cerebrospinal fluid (CSF) protein and cytokine levels, and brain immunohistochemistry for glial and white matter markers. RESULTS: I-Dendrimer demonstrated selective accumulation within brain lesions, co-localizing primarily with activated microglia. D-NAC significantly improved neurological outcomes and attenuated neuroinflammation and brain injury, even without antimicrobial therapy. Longitudinal PET imaging confirmed D-NAC efficacy, showing decreased neuroinflammation (I-DPA-713) and improved BBB integrity (F-py-albumin). Post-mortem analyses corroborated these findings, demonstrating that D-NAC reduced microglial inflammation and IL-17a levels, while improving myelination and BBB integrity. CONCLUSIONS: This study establishes D-NAC as a promising host-directed theranostic strategy for TB meningitis and supports the clinical potential of dendrimer nanoplatforms to diagnose and treat central nervous system infections.