Inflammation-induced Neuronal Damage in CNS Tuberculosis: Molecular Mechanism and Therapeutic Targets.

BACKGROUND

Central nervous system tuberculosis (CNS-TB), most frequently manifesting as tuberculous meningitis, is associated with high mortality and significant long-term neurological morbidity. Increasing evidence suggests that disease severity and neurological damage are driven largely by dysregulated host neuroinflammatory responses rather than direct Mycobacterium tuberculosis-mediated cytotoxicity. However, the mechanistic links between glial activation, inflammatory signaling, and neuronal injury remain incompletely defined.

MATERIALS AND

METHODS

A comprehensive literature review was conducted using PubMed, Scopus, and Web of Science databases to identify experimental, clinical, and translational studies investigating neuroimmune mechanisms in CNS-TB. Studies focusing on glial activation, cytokine signaling, oxidative stress, excitotoxicity, mitochondrial dysfunction, and neuronal death were included. Recent advances in single-cell transcriptomics, immunometabolism, and host-directed therapeutic strategies were also analyzed and integrated.

RESULTS

The reviewed evidence indicates that CNS invasion by M. tuberculosis leads to sustained activation of microglia and astrocytes, resulting in excessive production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. This inflammatory milieu disrupts blood-brain barrier (BBB) integrity, promotes leukocyte infiltration, and induces oxidative and nitrosative stress. Astrocyte dysfunction further contributes to excitotoxicity through impaired glutamate clearance. These converging inflammatory, oxidative, and excitotoxic pathways drive mitochondrial dysfunction, synaptic impairment, and activation of regulated neuronal cell death pathways, culminating in neurodegeneration.

CONCLUSION

CNS-TB-associated neuronal injury arises primarily from maladaptive host neuroimmune responses rather than direct mycobacterial effects. A unifying framework centered on glial-driven inflammation and mitochondrial dysfunction provides critical insight into disease pathogenesis. Targeting these convergent pathways through host-directed therapies, alongside antimicrobial treatment, represents a promising strategy to mitigate neuroinflammation and improve long-term neurological outcomes in CNS tuberculosis.