# Host-directed treatments for tuberculous meningitis: A multi-platform approach across mouse and human models

## TL;DR

This study explores new host-directed treatments for TB meningitis using mouse and human models, showing improved outcomes by reducing neuroinflammation.

## Contribution

A cross-species framework identifies novel immunomodulatory drugs that outperform current treatments for TB meningitis.

## Key findings

- New HDTs reduce mortality and neurological deficits in mice by suppressing neuroinflammation.
- HDTs significantly reduce microglial activation in human brain organoids infected with Mycobacterium tuberculosis.
- HDTs attenuate proinflammatory cytokines, especially IFNγ, in patient-derived PBMCs.

## Abstract

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. We identify new HDTs that outperform the current standard of care by reducing mortality and 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.