Abstract
BackgroundMeningitis 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.MethodsIn 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.ResultsGenome-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.DiscussionThe 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.
Highlights
Meningitis is a major cause of mortality in tuberculosis (TB)
Pando et al (2010) reported that BALB/c mice infected via the intra-tracheal route by Mycobacterium tuberculosis (Mtb) came down with meningitis when infected with isolates from cerebrospinal fluid (CSF) but not with isolates from sputum
The nine common genes we identified in UM-CSF strains and other mycobacterial spp. are mostly involved in cell membrane transport, signal transduction, nucleotide biosynthesis, and energy metabolism (Table 2)
Summary
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. 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. In parts of the world where the incidence of TB is high, TBM may occur in more than 10% of TB cases, especially among children and HIV infected individuals (Ige, Sogaolu & Ogunlade, 2005) The pathogenesis of this central nervous system (CNS) Mtb infection is still not clear. The sensor domain of Mtb pknD (Rv0931c) was able to trigger the invasion of brain endothelia but not the lung epithelia (Be, Bishai & Jain, 2012)
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