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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.

Chromosomal rearrangements and protein globularity changes inMycobacterium tuberculosisisolates from cerebrospinal fluid