Mycobacterium tuberculosis complex molecular networks and their regulation: Implications of strain heterogeneity on epigenetic diversity and transcriptome regulation

Tuberculosis has been a public health crisis since the 1900, which has caused the highest mortalities due to a single bacterial infection worldwide, that was recently further complicated by the Coronavirus disease 2019 pandemic. The causative agent of Tuberculosis, Mycobacterium tuberculosis, belongs to a genetically well-characterized family of strains known as the Mycobacterium tuberculosis complex, which has complicated progress made towards eradicating Tuberculosis due to pathogen-specific phenotypic differences in the members of this complex. Mycobacterium tuberculosis complex strains are genetically diverse human- and animal-adapted pathogens belonging to 7 lineages (Indo-Oceanic, East-Asian, East-African Indian, Euro-American, M. africanum West Africa 1, M. africanum West Africa 2 and Ethopia), respectively and the recently identified Lineage 8 and M. africanum Lineage 9. Genomic studies have revealed that Mycobacterium tuberculosis complex members are ∼99 % similar, however, due to selective pressure and adaptation to human host, they are prone to mutations that have resulted in development of drug resistance and phenotypic heterogeneity that impact strain virulence. Furthermore, members of the Mycobacterium tuberculosis complex have preferred geographic locations and possess unique phenotypic characteristics that is linked to their pathogenicity. Due to the recent advances in development next generation sequencing platforms, several studies have revealed epigenetic changes in genomic regions combined with “unique” gene regulatory mechanisms through non-coding RNAs that are responsible for strain-specific behaviour on in vitro and in vivo infection models. The current review provides up to date epigenetic patterns, gene regulation through non-coding RNAs, together with implications of these mechanisms in down-stream proteome and metabolome, which may be responsible for “unique” responses to infection by members of the Mycobacterium tuberculosis complex. Understanding lineage-specific molecular mechanisms during infection may provide novel drug targets and disease control measures towards World Health organization END-TB strategy.