Dataset Information

Molecular analysis of a leprosy immunotherapeutic bacillus provides insights into Mycobacterium evolution.

ABSTRACT: BACKGROUND: Evolutionary 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 FINDINGS: Genome 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/SIGNIFICANCE: This evolutionary paradigm possibly affirms to marshall our understanding about the acquisition and optimization of virulence in mycobacteria and determinants of boundaries therein.

SUBMITTER: Ahmed N

PROVIDER: S-EPMC1989137 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular analysis of a leprosy immunotherapeutic bacillus provides insights into Mycobacterium evolution.

Ahmed Niyaz N Saini Vikram V Raghuvanshi Saurabh S Khurana Jitendra P JP Tyagi Akhilesh K AK Tyagi Anil K AK Hasnain Seyed E SE

PloS one 20071003 10

<h4>Background</h4>Evolutionary 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 us ...[more]

PMID: 17912347

Similar Datasets

Project description:Bacillus mycoides is poorly known despite its frequent occurrence in a wide variety of environments. To provide direct insight into its ecology and evolutionary history, a comparative investigation of the species pan-genome and the functional gene categorization of 35 isolates obtained from soil samples from northeastern Poland was performed. The pan-genome of these isolates is composed of 20,175 genes and is characterized by a strong predominance of adaptive genes (∼83%), a significant amount of plasmid genes (∼37%), and a great contribution of prophages and insertion sequences. The pan-genome structure and phylodynamic studies had suggested a wide genomic diversity among the isolates, but no correlation between lineages and the bacillus origin was found. Nevertheless, the two B. mycoides populations, one from Białowieża National Park, the last European natural primeval forest with soil classified as organic, and the second from mineral soil samples taken in a farm in Jasienówka, a place with strong anthropogenic pressure, differ significantly in the frequency of genes encoding proteins enabling bacillus adaptation to specific stress conditions and production of a set of compounds, thus facilitating their colonization of various ecological niches. Furthermore, differences in the prevalence of essential stress sigma factors might be an important trail of this process. Due to these numerous adaptive genes, B. mycoides is able to quickly adapt to changing environmental conditions. IMPORTANCE This research allows deeper understanding of the genetic organization of natural bacterial populations, specifically, Bacillus mycoides, a psychrotrophic member of the Bacillus cereus group that is widely distributed worldwide, especially in areas with continental cold climates. These thorough analyses made it possible to describe, for the first time, the B. mycoides pan-genome, phylogenetic relationship within this species, and the mechanisms behind the species ecology and evolutionary history. Our study indicates a set of functional properties and adaptive genes, in particular, those encoding sigma factors, associated with B. mycoides acclimatization to specific ecological niches and changing environmental conditions.

Project description:Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern the underlying Darwinian dynamics. In three spontaneous murine cancers (prostate cancers in TRAMP and PTEN mice, pancreatic cancer in KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies that remained stable in culture: (i) invasive cells that produce an acidic environment via upregulated aerobic glycolysis; and (ii) noninvasive cells that were angiogenic and metabolically near-normal. Darwinian interactions of these subpopulations were investigated in TRAMP prostate cancers. Computer simulations demonstrated invasive, acid-producing (C2) cells maintain a fitness advantage over noninvasive, angiogenic (C3) cells by promoting invasion and reducing efficacy of immune response. Immunohistochemical analysis of untreated tumors confirmed that C2 cells were invariably more abundant than C3 cells. However, the C2 adaptive strategy phenotype incurred a significant cost due to inefficient energy production (i.e., aerobic glycolysis) and depletion of resources for adaptations to an acidic environment. Mathematical model simulations predicted that small perturbations of the microenvironmental extracellular pH (pHe) could invert the cost/benefit ratio of the C2 strategy and select for C3 cells. In vivo, 200 mmol/L NaHCO3 added to the drinking water of 4-week-old TRAMP mice increased the intraprostatic pHe by 0.2 units and promoted proliferation of noninvasive C3 cells, which remained confined within the ducts so that primary cancer did not develop. A 0.2 pHe increase in established tumors increased the fraction of C3 cells and signficantly diminished growth of primary and metastatic tumors. In an experimental tumor construct, MCF7 and MDA-MB-231 breast cancer cells were coinjected into the mammary fat pad of SCID mice. C2-like MDA-MB-231 cells dominated in untreated animals, but C3-like MCF7 cells were selected and tumor growth slowed when intratumoral pHe was increased. Overall, our data support the use of mathematical modeling of intratumoral Darwinian interactions of environmental selection forces and cancer cell adaptive strategies. These models allow the tumor to be steered into a less invasive pathway through the application of small but selective biological force. Cancer Res; 77(9); 2242-54. ©2017 AACR.

Dataset Information

Molecular analysis of a leprosy immunotherapeutic bacillus provides insights into Mycobacterium evolution.

Publications

Molecular analysis of a leprosy immunotherapeutic bacillus provides insights into Mycobacterium evolution.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets