Host-directed treatments for tuberculous meningitis utilizing a multi-platform approach across mouse and human models

Tuberculous meningitis (TB meningitis) is a major cause of death and neurological deficit despite recommended antibiotic and corticosteroid treatments, primarily due to dysregulated neuroinflammation. Here, we investigate a diverse panel of 12 immunomodulatory drugs as host-directed treatments (HDTs) for TB meningitis utilizing a cross-species framework comprising studies in a mouse model of TB meningitis with clinical endpoints, and parallel mechanistic studies in a newly developed immune-vascularized human brain organoid model of TB meningitis and peripheral blood mononuclear cells (PBMCs) from patients with TB meningitis. Imatinib, bestatin, roflumilast, palacaparib, thalidomide/pomalidomide and semaglutide outperform the current standard of care by reducing mortality and/or neurological deficits in mice via suppression of neuroinflammation. Importantly, these HDTs significantly reduce microglial activation in Mycobacterium tuberculosis-infected human brain organoids and attenuate proinflammatory cytokines, particularly IFNγ within CD4+ T-cells in patient-derived PBMCs. These findings highlight the potential of targeted HDTs to improve outcomes in TB meningitis and warrant clinical investigation.