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doi:10.1038/nindia.2012.137 Published online 21 September 2012

'Mosaic genome' holds clue to TB, leprosy vaccines

Subhra Priyadarshini

Scientists who recently decoded the complete genomic blueprint of Mycobacterium indicus pranii or MIP — a useful, non pathogenic organism — have been astonished to find that more than half of its genome is actually derived from other organisms, making it an interesting case of a 'mosaic genome'1. Their surprise stems from the fact that until now, this genus of 'mycobacteria' that includes notorious pathogens were considered to be rigid organisms with very less gene exchange.

The researchers: (clockwise from top left) Vikram Saini, Anil Tyagi, Seyed Hasnain, Saurabh Raghuvanshi, Jitendra Khurana, Niyaz Ahmed & Akhilesh Tyagi.

Comparing the genomic blueprint of all the 18 mycobacterial species with their great grandpa or evolutionary ancestor MIP, they found that more than 50% of the MIP genome was derived from other organisms. "This is a major conceptual advance. Studying the evolution of this species can help uncover clues to new treatment or vaccines against TB and leprosy," lead researcher Vikram Saini told Nature India.

MIP, which is not a pathogen, has shown protective benefits in diseases like leprosy, TB, TB-HIV co-infection and some cancers in clinical trials. In multi drug resistant TB — a dangerous form of TB where treatment could stretch beyond two years — MIP provides better clinical outcomes and reduces the time of therapy. MIP does this by stimulating the human immune system to mount an effective immune response against these infections or diseases.

However, very little information was available about the genetic components of this organism that are responsible for its non-pathogenic nature and its role in perking up immunity.

Saini says information on what genes were exchanged with other organisms to evolve from a non-pathogenic to a pathogenic lifestyle is critical. "One step forward will be to study these genes in detail as they can be potential new drug targets," he says.

The scientists attempted to address a long standing question — how do mycobacterial organisms turn into deadly pathogens from their humble soil-derived ancestors? The comparison of MIP genome with the genomes of other mycobacterial organisms helped them identify genes absent from MIP that help it attain a non-pathogenic nature.

"We now have an understanding for the first time as to how mycobacteria acquire specific genes and lose some to attain their host adapted forms causing infections in a variety of hosts including humans and animals", co-author Anil Tyagi told Nature India. The scientists also know how gain and loss of specific genes lead to evolution of new mycobacterial strains including the drug resistant forms. Understanding evolution and controlling the factors promoting evolution of these constantly adapting bacteria could be a very effective way to control diseases.

Earlier, the scientists completely decoded the genomic blueprint of MIP2 and identified the beneficial proteins. "Several new antigenic proteins that we identified in MIP are incidentally absent from the vaccine strain BCG but present in both Mycobacterium leprae and Mycobacterium tuberculosis," Tyagi says.

"Using modern biotechnology tools, these genes can be transferred to the BCG strain to boost its immune potential and to develop a common vaccine for both TB and leprosy," he adds. This will be a boon for public health and diseases control considering both TB and leprosy are widespread in India.

"We are also facing the emergence of resistant forms of TB and the combined threat from HIV/TB pandemic. We urgently need new drugs, new vaccines and new strategies to overcome these challenges to public health," Saini says.

During their comparative studies, the researchers found that the prominent 'generalist' pathogen M. avium — a big threat to AIDS patients — descended from MIP as did its close associate M. avium paratuberculosis (MAP)3, the agent of Crohn's disease in humans and Johne's disease in cattle, according to co-author Niyaz Ahmed.

The knowledge of genome repertoire and antigenic proteins of MIP will help in making full use of its immune potential and will be crucial to the development of MIP as a mainstream therapeutic vaccine against these human infections.

The MIP bacilli, also called Mycobacterium w (Mw), were first isolated in India by G. P. Talwar at the All India Institute of Medical Sciences, New Delhi in the eighties and are currently used, after an extensive clinical trial, as an immunotherapeutic against leprosy in India. The success with MIP- based leprosy vaccine has led to human clinical evaluations of MIP in interventions against HIV-AIDS, psoriasis and bladder cancer in India.

The authors of this work are from: Interdisciplinary Centre for Plant Genomics and Department of Plant Molecular Biology, University of Delhi South Campus, New Delhi; School of Life Sciences, University of Hyderabad, Andhra Pradesh; School of Biological Sciences, Indian Institute of Technology, New Delhi; Institute of Life Sciences, University of Hyderabad Campus, Andhra Pradesh; and National Institute of Plant Genome Research, New Delhi, India.


References

  1. Saini, V. et al. Massive gene acquisitions in Mycobacterium indicus pranii provide a perspective on mycobacterial evolution. Nucl. Acid Res. doi: 10.1093/nar/gks793 (2012)
  2. Ahmed, N. et al. Molecular analysis of a leprosy immunotherapeutic bacillus provides insights into Mycobacterium. PLoS ONE doi: 10.1371/journal.pone.0000968 (2007)
  3. Indian bug great grandpa to Crohn's disease pathogen. Nature India. doi: 10.1038/nindia.2007.24 (2007)