The evidence regarding whether tuberculosis bacteria directly damage blood vessels is mixed. Some experimental studies and in vitro models indicate that M. tuberculosis can directly disrupt blood-brain barrier structures and induce vascular damage, while other literature suggests that tissue and vascular injury are primarily driven by host-mediated inflammatory and immune responses rather than direct bacterial cytotoxicity.
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 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.
Tuberculosis (TB) of the central nervous system (CNS) presents high mortality due to brain damage and inflammation events. The formation and deposition of immune complexes (ICs) in the brain microvasculature during Mycobacterium tuberculosis (Mtb) infection are crucial for its pathobiology. The relevance of ICs to Mtb antigens in the pathogenesis of CNS-TB has been poorly explored. Here, we aimed to establish a murine experimental model of ICs-mediated brain vasculitis induced by cell wall antigens of Mtb. We administered a cell wall extract of the prototype pathogenic Mtb strain H37Rv to male BALB/c mice by subcutaneous and intravenous routes. Serum concentration and deposition of ICs onto blood vessels were determined by polyethylene glycol precipitation, ELISA, and immunofluorescence. Histopathological changes in the brain, lung, spleen, liver, and kidney were evaluated by hematoxylin and eosin staining. Our results evidenced that vasculitis developed in the studied tissues. High serum levels of ICs and vascular deposition were evident in the brain, lung, and kidneys early after the last cell wall antigen administration. Cell wall Mtb antigens induce strong type III hypersensitivity reactions and the development of systemic vasculitis with brain vascular changes and meningitis, supporting a role for ICs in the pathogenesis of TB.
Central nervous system tuberculosis (CNSTB) is the most serious manifestation of extrapulmonary tuberculosis infections representing 5–10% of all cases. How Mycobacterium tuberculosis (Mtb) crosses the highly regulated blood-brain barrier (BBB) and enters the CNS, is still not well understood. We showed previously that mycobacterium infected dendritic cells adhere to brain microvessel endothelial cells. Here, we applied a novel model of in vitro BBB consisting of primary brain astrocytes and microvessel endothelial cells to test the mechanisms of how mycobacterium infected dendritic cells (DCs) interact with peripheral blood mononuclear cells (PBMC) and affect the BBB. We show that infected DC migration was hindered but infected DCs induce cellular cluster formations containing PMBC and T cells in addition to DCs. These clusters contained 24% CD11c+, 57%CD11b+, and 16% CD4+ cells, while B220+ B cell number was negligible mimicking the cellular composition of pulmonary granulomatous-like lesions. PBMC and infected DC clusters strongly adhered to the in vitro BBB and induced cluster associated damage (CAD). CAD correlated with mitochondrial disorganization and the degradation of ZO-1, claudin-5 tight junction associated proteins, upregulation of cellular adhesion molecules VCAM-1 and ICAM-1 in endothelial cells. Anti-TNF-a inhibition reduced cluster formation as well as ICAM-1 expression on brain microvessel endothelial cells and mitigated CAD. This research will lead to better knowledge in understanding how mycobacteria affects the BBB that could lead to better therapeutic treatments for CNSTB infection.
Everything we examined (4)
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