Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

Abstract

<ns4:p>The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of &lt;150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts &gt; 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.</ns4:p>

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

“…Although NAATs are a major diagnostic advance, they are still inadequate to replace culture methods. The CRISPR- M. tuberculosis and metagenomic next-generation sequencing (mNGS) technologies (reviewed in reference 63 ), may improve the detection of M. tuberculosis in CSF samples with low bacillary load. However, further investigations are required to ascertain the performance of these methods.…”

Nanoparticle delivery through the BBB in central nervous system tuberculosis

“…Although the mechanism(s) driving CNS‐TB physiopathology are not yet fully elucidated, CNS destruction has been linked to a disequilibrium of pro‐inflammatory and anti‐inflammatory cytokines, which depends on the bacillary load 110,113 . In more detail, a high CSF bacillary load has been associated with severe CNS‐TB and a two‐fold increase in mortality, while patients with low CSF bacillary load have a lower risk of death and may benefit from additional supportive care 110,114,115 …”

Tuberculous Meningitis in Children: Reducing the Burden of Death and Disability

“…Whether the mycobacteria are contained or cause clinical disease, and the extent of clinical disease, is determined by an interplay of host immune response and M. tuberculosis virulence factors, however our understanding of these processes remains incomplete. Studies in paediatric [12][13][14] and adult TBM [13] demonstrate associations between immune mediators and clinical outcome, and suggest that a disequilibrium of pro-and anti-inflammatory cytokines underlies the severity and course of TBM. This balance can be regulated by Leukotriene A4 Hydroxylase (LTA4H); a gene that encodes an enzyme which influences the balance of pro-and anti-inflammatory eicosanoids seen in intracerebral inflammation.…”

“…This balance can be regulated by Leukotriene A4 Hydroxylase (LTA4H); a gene that encodes an enzyme which influences the balance of pro-and anti-inflammatory eicosanoids seen in intracerebral inflammation. Variations of the LTA4H genotype may contribute to heterogeneity of the inflammatory response and outcomes in TBM [15] Studies are ongoing to further examine the role of the LTA4H genotype on the immunoinflammatory response and the possibility of personalising adjunctive anti-inflammatory therapy based on host genotype [13] Clues to further understanding the biology of cerebral injury in TBM have come from biomarker signatures in TBM-infected children presenting with stroke [1,14] and transcriptional profiles demonstrating compartmentalisation of the immune response within the CNS (ventricular vs. lumbar CSF) [16].…”