Abstract
BackgroundEvolutionary dynamics plays a central role in facilitating the mechanisms of species divergence among pathogenic and saprophytic mycobacteria. The ability of mycobacteria to colonize hosts, to proliferate and to cause diseases has evolved due to its predisposition to various evolutionary forces acting over a period of time. Mycobacterium indicus pranii (MIP), a taxonomically unknown ‘generalist’ mycobacterium, acts as an immunotherapeutic against leprosy and is approved for use as a vaccine against it. The large-scale field trials of this MIP based leprosy vaccine coupled with its demonstrated immunomodulatory and adjuvant property has led to human clinical evaluations of MIP in interventions against HIV-AIDS, psoriasis and bladder cancer. MIP, commercially available as ‘Immuvac’, is currently the focus of advanced phase III clinical trials for its antituberculosis efficacy. Thus a comprehensive analysis of MIP vis-à-vis evolutionary path, underpinning its immanent immunomodulating properties is of the highest desiderata.Principal FindingsGenome wide comparisons together with molecular phylogenetic analyses by fluorescent amplified fragment length polymorphism (FAFLP), enterobacterial repetitive intergenic consensus (ERIC) based genotyping and candidate orthologues sequencing revealed that MIP has been the predecessor of highly pathogenic Mycobacterium avium intracellulare complex (MAIC) that did not resort to parasitic adaptation by reductional gene evolution and therefore, preferred a free living life-style. Further analysis suggested a shared aquatic phase of MAIC bacilli with the early pathogenic forms of Mycobacterium, well before the latter diverged as ‘specialists’.Conclusions/SignificanceThis evolutionary paradigm possibly affirms to marshal our understanding about the acquisition and optimization of virulence in mycobacteria and determinants of boundaries therein.
Highlights
Genus Mycobacterium represents some of man’s most potent microbiological adversaries like M. tuberculosis (MTB), the tuberculosis (TB) causing bacterium that is responsible for the loss of more than 50,000 human lives every week, globally
The three principle genetic groups (PGG) based on the single nucleotide polymorphisms of katG 463CTG (Leu) and gyrA 95ACC (Thr) (15) showed that Mycobacterium indicus pranii (MIP) and Mycobacterium avium intracellulare complex (MAIC) bacilli belong to group 1 that includes pathogenic branch members like M. marinum, M. ulcerans and MTB W-Beijing strain
The analyses revealed that MIP has shown a congruent pattern of regions of deletions (RDs)’s with respect to the members of MAIC and a similar pattern with that of early pathogenic members of M. tuberculosis complex (MTBC) like M. marinum and M. ulcerans
Summary
Genus Mycobacterium represents some of man’s most potent microbiological adversaries like M. tuberculosis (MTB), the tuberculosis (TB) causing bacterium that is responsible for the loss of more than 50,000 human lives every week, globally. MIP, commercially available as ‘‘Immuvac’’ vaccine, exhibited immunoprophylactic benefits in household contacts of leprosy patients in the largest ever clinical trial in India [8]. It shares antigens with M. leprae and M. tuberculosis and provides protection to both BCG responder and non-responder genetic strains of mice against M. tuberculosis H37Rv infection [9]. The large-scale field trials of this MIP based leprosy vaccine coupled with its demonstrated immunomodulatory and adjuvant property has led to human clinical evaluations of MIP in interventions against HIV-AIDS, psoriasis and bladder cancer. This evolutionary paradigm possibly affirms to marshal our understanding about the acquisition and optimization of virulence in mycobacteria and determinants of boundaries therein
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