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Differential gene repertoire in Mycobacterium ulcerans identifies candidate genes for patho-adaptation.

Käser M, Pluschke G - PLoS Negl Trop Dis (2008)

Bottom Line: Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans.The differential gene inactivation patterns associated with the M. ulcerans haplotypes identified candidate genes that may confer enhanced adaptation upon ablation of expression.Identification of this spectrum of anti-virulence gene candidates expands our understanding of the pathogenicity and ecology of the emerging infectious disease Buruli ulcer.

View Article: PubMed Central - PubMed

Affiliation: Swiss Tropical Institute, Basel, Switzerland. m.kaeser@unibas.ch

ABSTRACT

Background: Based on large genomic sequence polymorphisms, several haplotypes belonging to two major lineages of the human pathogen Mycobacterium ulcerans could be distinguished among patient isolates from various geographic origins. However, the biological relevance of insertional/deletional diversity is not understood.

Methodology: Using comparative genomics, we have investigated the genes located in regions of difference recently identified by DNA microarray based hybridisation analysis. The analysed regions of difference comprise approximately 7% of the entire M. ulcerans genome.

Principal findings: Several different mechanisms leading to loss of functional genes were identified, ranging from pseudogenization, caused by frame shift mutations or mobile genetic element interspersing, to large sequence polymorphisms. Four hot spot regions for genetic instability were unveiled. Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans.

Conclusions/significance: The differential gene inactivation patterns associated with the M. ulcerans haplotypes identified candidate genes that may confer enhanced adaptation upon ablation of expression. A number of gene conversions confined to the classical lineage may contribute to particular virulence of this group comprising isolates from Africa and Australia. Identification of this spectrum of anti-virulence gene candidates expands our understanding of the pathogenicity and ecology of the emerging infectious disease Buruli ulcer.

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Genomic events leading to strain variations and pathogen emergence in M. ulcerans haplotypes.
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pntd-0000353-g005: Genomic events leading to strain variations and pathogen emergence in M. ulcerans haplotypes.

Mentions: M. marinum causes only occasionally ulcerative but self-healing infections in humans [37]. Without doubt, the acquisition of the virulence plasmid and the expression of the macrolide toxin mycolactone was an important step in the development of the ancestor of M. ulcerans to a mammalian pathogen [17]. On the other hand, other mycolactone producing mycobacteria closely related to M. marinum and M. ulcerans have been recently isolated from lesions in frogs and fish [38],[39] but so far not from infected humans. This indicates that additional factors contribute to the high virulence of the classical lineage of M. ulcerans. Our data indicate that, in addition to “gain of function” by acquisition of the virulence plasmid, loss of distinct anti-virulence genes, partly driven by ISE – in particular IS2606 – expansion, might have equipped the classical lineage with a particular virulence and transmissibility (Fig. 5). It would be interesting to experimentally verify this hypothesis by testing these newly identified anti-virulence candidates in an appropriate in vivo model.


Differential gene repertoire in Mycobacterium ulcerans identifies candidate genes for patho-adaptation.

Käser M, Pluschke G - PLoS Negl Trop Dis (2008)

Genomic events leading to strain variations and pathogen emergence in M. ulcerans haplotypes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600814&req=5

pntd-0000353-g005: Genomic events leading to strain variations and pathogen emergence in M. ulcerans haplotypes.
Mentions: M. marinum causes only occasionally ulcerative but self-healing infections in humans [37]. Without doubt, the acquisition of the virulence plasmid and the expression of the macrolide toxin mycolactone was an important step in the development of the ancestor of M. ulcerans to a mammalian pathogen [17]. On the other hand, other mycolactone producing mycobacteria closely related to M. marinum and M. ulcerans have been recently isolated from lesions in frogs and fish [38],[39] but so far not from infected humans. This indicates that additional factors contribute to the high virulence of the classical lineage of M. ulcerans. Our data indicate that, in addition to “gain of function” by acquisition of the virulence plasmid, loss of distinct anti-virulence genes, partly driven by ISE – in particular IS2606 – expansion, might have equipped the classical lineage with a particular virulence and transmissibility (Fig. 5). It would be interesting to experimentally verify this hypothesis by testing these newly identified anti-virulence candidates in an appropriate in vivo model.

Bottom Line: Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans.The differential gene inactivation patterns associated with the M. ulcerans haplotypes identified candidate genes that may confer enhanced adaptation upon ablation of expression.Identification of this spectrum of anti-virulence gene candidates expands our understanding of the pathogenicity and ecology of the emerging infectious disease Buruli ulcer.

View Article: PubMed Central - PubMed

Affiliation: Swiss Tropical Institute, Basel, Switzerland. m.kaeser@unibas.ch

ABSTRACT

Background: Based on large genomic sequence polymorphisms, several haplotypes belonging to two major lineages of the human pathogen Mycobacterium ulcerans could be distinguished among patient isolates from various geographic origins. However, the biological relevance of insertional/deletional diversity is not understood.

Methodology: Using comparative genomics, we have investigated the genes located in regions of difference recently identified by DNA microarray based hybridisation analysis. The analysed regions of difference comprise approximately 7% of the entire M. ulcerans genome.

Principal findings: Several different mechanisms leading to loss of functional genes were identified, ranging from pseudogenization, caused by frame shift mutations or mobile genetic element interspersing, to large sequence polymorphisms. Four hot spot regions for genetic instability were unveiled. Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans.

Conclusions/significance: The differential gene inactivation patterns associated with the M. ulcerans haplotypes identified candidate genes that may confer enhanced adaptation upon ablation of expression. A number of gene conversions confined to the classical lineage may contribute to particular virulence of this group comprising isolates from Africa and Australia. Identification of this spectrum of anti-virulence gene candidates expands our understanding of the pathogenicity and ecology of the emerging infectious disease Buruli ulcer.

Show MeSH
Related in: MedlinePlus