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Updated: Jul 31, 2026
A Tuberculosis Molecular Bacterial Load Assay TB-MBLA
Published on: April 30, 2020
Chromosomal rearrangements and protein globularity changes in Mycobacterium tuberculosis isolates from cerebrospinal
Seow Hoon Saw1,2, Joon Liang Tan3,4, Xin Yue Chan5
1Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Bandar Sungai Long, Malaysia.
Background:
Meningitis is a major cause of mortality in tuberculosis (TB). It is not clear what factors promote central nervous system invasion and pathology but it has been reported that certain strains of Mycobacterium tuberculosis (Mtb) might have genetic traits associated with neurotropism.
Methods:
In this study, we generated whole genome sequences of eight clinical strains of Mtb that were isolated from the cerebrospinal fluid (CSF) of patients presenting with tuberculous meningitis (TBM) in Malaysia, and compared them to the genomes of H37Rv and other respiratory Mtb genomes either downloaded from public databases or extracted from local sputum isolates. We aimed to find genomic features that might be distinctly different between CSF-derived and respiratory Mtb.
Results:
Genome-wide comparisons revealed rearrangements (translocations, inversions, insertions and deletions) and non-synonymous SNPs in our CSF-derived strains that were not observed in the respiratory Mtb genomes used for comparison. These rearranged segments were rich in genes for PE (proline-glutamate)/PPE (proline-proline-glutamate), transcriptional and membrane proteins. Similarly, most of the ns SNPs common in CSF strains were noted in genes encoding PE/PPE proteins. Protein globularity differences were observed among mycobacteria from CSF and respiratory sources and in proteins previously reported to be associated with TB meningitis. Transcription factors and other transcription regulators featured prominently in these proteins. Homologs of proteins associated with Streptococcus pneumoniae meningitis and Neisseria meningitidis virulence were identified in neuropathogenic as well as respiratory mycobacterial spp. examined in this study.
Discussion:
The occurrence of in silico genetic differences in CSF-derived but not respiratory Mtb suggests their possible involvement in the pathogenesis of TBM. However, overall findings in this comparative analysis support the postulation that TB meningeal infection is more likely to be related to the expression of multiple virulence factors on interaction with host defences than to CNS tropism associated with specific genetic traits.
Insights
Genetic differences in Mycobacterium tuberculosis (Mtb) strains from cerebrospinal fluid (CSF) may contribute to tuberculous meningitis (TBM) pathogenesis. However, TBM likely results from multiple virulence factors interacting with host defenses, not just specific genetic traits for CNS invasion.
Area of Science:
- Genomics and Molecular Biology
- Infectious Diseases
- Neuroscience
Background:
- Tuberculosis (TB) meningitis is a significant cause of mortality.
- The factors enabling Mycobacterium tuberculosis (Mtb) central nervous system (CNS) invasion and pathology remain unclear.
- Specific Mtb genetic traits potentially linked to neurotropism have been suggested.
Purpose of the Study:
- To identify distinct genomic features in Mtb strains isolated from cerebrospinal fluid (CSF) compared to respiratory Mtb.
- To investigate potential genetic underpinnings of Mtb's ability to cause tuberculous meningitis (TBM).
Main Methods:
- Whole genome sequencing of eight clinical Mtb strains from TBM patients' CSF in Malaysia.
- Comparative analysis against reference H37Rv and local respiratory Mtb genomes.
- Identification of genomic rearrangements and non-synonymous single nucleotide polymorphisms (SNPs).
Main Results:
- CSF-derived Mtb strains exhibited unique genome-wide rearrangements and non-synonymous SNPs compared to respiratory strains.
- Rearranged segments and SNPs were frequently found in genes encoding PE/PPE proteins, transcriptional regulators, and membrane proteins.
- Protein globularity differences were observed, with homologs of known bacterial meningitis virulence proteins identified.
Conclusions:
- In silico identified genetic differences in CSF-derived Mtb suggest a potential role in TBM pathogenesis.
- The study supports the hypothesis that TBM is more likely driven by the interplay of multiple virulence factors with host defenses.
- Specific genetic traits for CNS tropism may be less critical than the expression of diverse virulence factors in TBM.
