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<p>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 <i>Mycobacterium tuberculosis</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Carlos E. Ruiz-Gonzalez,
  • Medha Singh,
  • Yuderleys Masias-Leon,
  • Xueyi Chen,
  • Mona O. Sarhan,
  • Yazmin B. Martinez-Martinez,
  • Sruti Patel,
  • Madelynn Shambles,
  • Andres Villabona-Rueda,
  • Kadia Lissit,
  • David Tweedie,
  • Michael T. Scerba,
  • William R. Bishai,
  • Dmitri Artemov,
  • Jin-Chong Xu,
  • Franco D’Alessio,
  • Richard Hafner,
  • Nigel H. Greig,
  • Maura Manion,
  • Irini Sereti,
  • Sanjay K. Jain

摘要

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.