Molecular Analysis of a Leprosy Immunotherapeutic Bacillus Provides Insights into Mycobacterium Evolution

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.

The Genealogic Tree of Mycobacteria Reveals a Long-Standing Sympatric Life into Free-Living Protozoa

“…This hypothesis agrees with the current model for the evolution of mycobacteria, which postulates that the ancestor of mycobacteria was an environmental organism living in an aquatic habitat [50]. Recent genome analysis of the environmental Mycobacterium indicus pranii , a member of the M. avium complex, further supports this hypothesis in which the most recent common ancestor of mycobacteria gave rise to waterborne M. marinum and M. ulcerans on one branch, the M. avium complex on a second branch and the M. tuberculosis complex on a third branch [50].…”

Extraordinary solute‐stress tolerance contributes to the environmental tenacity of mycobacteria

“…It has been often commented that mycobacteria have a distinctive and complex ecology; some species or strains are specialists, some are generalists and others may be neither specialist nor generalist in their lifestyle (Ahmed et al ., ). Whereas Mycobacterium is a genus of mesophilic species based on the conditions required for optimum growth, our data suggest that certain mycobacteria are as resilient to key solute‐induced stresses as some of the most stress‐tolerant microbes known to science.…”

Free-living amoebae, a training field for macrophage resistance of mycobacteria

“…Mycobacteria are mycolic acid‐containing, high guanine‐cytosine‐content bacterial organisms belonging to the Actinobacteria phylum [1]. Comparative genomics indicated that the most recent common ancestor of Mycobacteria was an environmental species [2,3] which evolved towards soil‐borne mycobacteria, waterborne mycobacteria such as Mycobacterium avium , Mycobacterium intracellulare, and host‐associated species including M. avium subsp. paratuberculosis and Mycobacterium avium subsp.…”