Tuberculous Meningitis: Pathogenesis, Immune Responses, Diagnostic Challenges, and the Potential of Biomarker-Based Approaches

Abstract

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis (TB), causing high mortality or disability. Clinical management of the disease is challenging due to limitations of the existing diagnostic approaches. Our knowledge on the immunology and pathogenesis of the disease is currently limited. More research is urgently needed to enhance our understanding of the immunopathogenesis of the disease and guide us toward the identification of targets that may be useful for vaccines or host-directed therapeutics. In this review, we summarize the current knowledge about the immunology and pathogenesis of TBM and summarize the literature on existing and new, especially biomarker-based, approaches that may be useful in the management of TBM. We identify research gaps and provide directions for research which may lead to the development of new tools for the control of the disease in the near future.

Keywords: biomarker; central nervous system infections; diagnosis; immune response; meningitis; pathogenesis; tuberculosis; tuberculous meningitis.

FIG 1

The generalized pathogenesis of tuberculous meningitis. (a) The host inhales aerosol droplets containing M. tuberculosis (Mtb) bacilli. Within the lungs, the bacilli may infect the alveolar macrophages, resulting in the formation of granuloma. The bacilli may then escape from a damaged granuloma or from the lungs during primary TB causing bacteremia, resulting in hematogenous spread of the bacteria into the brain. (b) Extracellular bacteria and infected cells may migrate through the blood-brain barrier (BBB) into the brain. Once in the brain, the bacilli infect microglial cells, which then together with infiltrating cells release cytokines and chemokines, leading to disruption of the BBB and influx of other uninfected immune cells into the brain. (c) This results in the formation of the granuloma “Rich focus.” (d) When the Rich focus ruptures, the bacteria are released into the subarachnoid space, leading to dissemination of the infection to the CSF and meninges. The release of bacteria into the meninges and CSF leads to meningeal inflammation and the formation of thick exudate. The thick exudate precipitates TBM signs.