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Host-pathogen o-methyltransferase similarity and its specific presence in highly virulent strains of Francisella tularensis suggests molecular mimicry.

Champion MD - PLoS ONE (2011)

Bottom Line: In highly clonal species that share the bulk of their genomes subtle changes in gene content and small-scale polymorphisms, especially those that may alter gene expression and protein-protein interactions, are more likely to have a significant effect on the pathogen's biology.Altogether, evidence suggests a role of the F. t. subsp. tularensis protein in a mechanism of molecular mimicry, similar perhaps to Legionella and Coxiella.These findings therefore provide insights into the evolution of niche-restriction and virulence in Francisella, and have broader implications regarding the molecular mechanisms that mediate host-pathogen relationships.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathogen Genomics, Translational Genomics Research Institute, Arizona, United States of America. mchampion@tgen.org

ABSTRACT
Whole genome comparative studies of many bacterial pathogens have shown an overall high similarity of gene content (>95%) between phylogenetically distinct subspecies. In highly clonal species that share the bulk of their genomes subtle changes in gene content and small-scale polymorphisms, especially those that may alter gene expression and protein-protein interactions, are more likely to have a significant effect on the pathogen's biology. In order to better understand molecular attributes that may mediate the adaptation of virulence in infectious bacteria, a comparative study was done to further analyze the evolution of a gene encoding an o-methyltransferase that was previously identified as a candidate virulence factor due to its conservation specifically in highly pathogenic Francisella tularensis subsp. tularensis strains. The o-methyltransferase gene is located in the genomic neighborhood of a known pathogenicity island and predicted site of rearrangement. Distinct o-methyltransferase subtypes are present in different Francisella tularensis subspecies. Related protein families were identified in several host species as well as species of pathogenic bacteria that are otherwise very distant phylogenetically from Francisella, including species of Mycobacterium. A conserved sequence motif profile is present in the mammalian host and pathogen protein sequences, and sites of non-synonymous variation conserved in Francisella subspecies specific o-methyltransferases map proximally to the predicted active site of the orthologous human protein structure. Altogether, evidence suggests a role of the F. t. subsp. tularensis protein in a mechanism of molecular mimicry, similar perhaps to Legionella and Coxiella. These findings therefore provide insights into the evolution of niche-restriction and virulence in Francisella, and have broader implications regarding the molecular mechanisms that mediate host-pathogen relationships.

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O-methyltransferase orthologs are located proximal to predicted genome rearrangements.A) Dotplot comparison of pairwise alignments between whole-genome sequences from representatives of various Francisella subspecies is shown. The o-methyltransferase ortholog is highlighted on the Francisella tularensis subsp. holarctica strain 257 in orange (Y-axis) and on the Francisella tularensis subsp tularensis SchuS4 strain (X-axis, reference genome) in red. Blocks of synteny between each of the Francisella genomes compared to the Francisella tularensis subsp tularensis SchuS4 strain are plotted and rearrangements are indicated by breaks in the linearity of the lines and perpendicular orientations.
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pone-0020295-g004: O-methyltransferase orthologs are located proximal to predicted genome rearrangements.A) Dotplot comparison of pairwise alignments between whole-genome sequences from representatives of various Francisella subspecies is shown. The o-methyltransferase ortholog is highlighted on the Francisella tularensis subsp. holarctica strain 257 in orange (Y-axis) and on the Francisella tularensis subsp tularensis SchuS4 strain (X-axis, reference genome) in red. Blocks of synteny between each of the Francisella genomes compared to the Francisella tularensis subsp tularensis SchuS4 strain are plotted and rearrangements are indicated by breaks in the linearity of the lines and perpendicular orientations.

Mentions: It seemed relevant to next analyze the genomic context of the gene sequences in order to evaluate how recombination and selection may have influenced the evolution of several distinct o-methyltransferase subtypes that are highly conserved within independent subspecies of Francisella. In F. tularensis subsp. tularensis , the FTT1766 locus spans a 656 nucleotide region of the genome (bp 1853414–1854070) and is in the genomic neighborhood of one copy of the duplicated pathogenicity islands, comprising a ∼33.9 kb region at around bp 1,800,000 of the genome [14]. Mutations of several genes within the pathogenicity islands have been shown in previous studies to significantly reduce the pathogens ability to survive within amoebae or macrophage hosts. In addition, specific families of Insertion Sequence Elements (ISFtu1 and ISFtu2) are enriched in the more pathogenic species of Francisella and previous studies have provided evidence that IS Element-based genome rearrangement events led to the duplication of the pathogenicity islands in the F. tularensis lineage [15]. Genome rearrangements proximal to the o-methyltransferase locus are evident from whole genome alignments and dotplot comparisons between representatives of various Francisella subspecies (Figure 4). The PHI test did not find statistically significant evidence for recombination between gene copies (p = 0.826) [28]. It was thus relevant to assess whether functional differentiation has been mediated by a molecular adaptation process acting on the coding region of the o-methyltransferase locus. Methods which estimate the ratio of the rates of non-synonymous (dN) to synonymous (dS) substitutions can be used to distinguish pseudogene evolution from positive selection; the former is evident by a dN/dS ratio approaching 1 across the length of the gene, rather than several sites within the gene exhibiting a dN/dS ratio >1 [29]. Multiple alignments of the Francisella homologous o-methyltransferase sequences were analyzed for evidence of pseudogene evolution and positive selection [30]. Different models identified several of the same sites, however, the statistical significance was not consistent enough to provide definitive evidence of positive selection.


Host-pathogen o-methyltransferase similarity and its specific presence in highly virulent strains of Francisella tularensis suggests molecular mimicry.

Champion MD - PLoS ONE (2011)

O-methyltransferase orthologs are located proximal to predicted genome rearrangements.A) Dotplot comparison of pairwise alignments between whole-genome sequences from representatives of various Francisella subspecies is shown. The o-methyltransferase ortholog is highlighted on the Francisella tularensis subsp. holarctica strain 257 in orange (Y-axis) and on the Francisella tularensis subsp tularensis SchuS4 strain (X-axis, reference genome) in red. Blocks of synteny between each of the Francisella genomes compared to the Francisella tularensis subsp tularensis SchuS4 strain are plotted and rearrangements are indicated by breaks in the linearity of the lines and perpendicular orientations.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102702&req=5

pone-0020295-g004: O-methyltransferase orthologs are located proximal to predicted genome rearrangements.A) Dotplot comparison of pairwise alignments between whole-genome sequences from representatives of various Francisella subspecies is shown. The o-methyltransferase ortholog is highlighted on the Francisella tularensis subsp. holarctica strain 257 in orange (Y-axis) and on the Francisella tularensis subsp tularensis SchuS4 strain (X-axis, reference genome) in red. Blocks of synteny between each of the Francisella genomes compared to the Francisella tularensis subsp tularensis SchuS4 strain are plotted and rearrangements are indicated by breaks in the linearity of the lines and perpendicular orientations.
Mentions: It seemed relevant to next analyze the genomic context of the gene sequences in order to evaluate how recombination and selection may have influenced the evolution of several distinct o-methyltransferase subtypes that are highly conserved within independent subspecies of Francisella. In F. tularensis subsp. tularensis , the FTT1766 locus spans a 656 nucleotide region of the genome (bp 1853414–1854070) and is in the genomic neighborhood of one copy of the duplicated pathogenicity islands, comprising a ∼33.9 kb region at around bp 1,800,000 of the genome [14]. Mutations of several genes within the pathogenicity islands have been shown in previous studies to significantly reduce the pathogens ability to survive within amoebae or macrophage hosts. In addition, specific families of Insertion Sequence Elements (ISFtu1 and ISFtu2) are enriched in the more pathogenic species of Francisella and previous studies have provided evidence that IS Element-based genome rearrangement events led to the duplication of the pathogenicity islands in the F. tularensis lineage [15]. Genome rearrangements proximal to the o-methyltransferase locus are evident from whole genome alignments and dotplot comparisons between representatives of various Francisella subspecies (Figure 4). The PHI test did not find statistically significant evidence for recombination between gene copies (p = 0.826) [28]. It was thus relevant to assess whether functional differentiation has been mediated by a molecular adaptation process acting on the coding region of the o-methyltransferase locus. Methods which estimate the ratio of the rates of non-synonymous (dN) to synonymous (dS) substitutions can be used to distinguish pseudogene evolution from positive selection; the former is evident by a dN/dS ratio approaching 1 across the length of the gene, rather than several sites within the gene exhibiting a dN/dS ratio >1 [29]. Multiple alignments of the Francisella homologous o-methyltransferase sequences were analyzed for evidence of pseudogene evolution and positive selection [30]. Different models identified several of the same sites, however, the statistical significance was not consistent enough to provide definitive evidence of positive selection.

Bottom Line: In highly clonal species that share the bulk of their genomes subtle changes in gene content and small-scale polymorphisms, especially those that may alter gene expression and protein-protein interactions, are more likely to have a significant effect on the pathogen's biology.Altogether, evidence suggests a role of the F. t. subsp. tularensis protein in a mechanism of molecular mimicry, similar perhaps to Legionella and Coxiella.These findings therefore provide insights into the evolution of niche-restriction and virulence in Francisella, and have broader implications regarding the molecular mechanisms that mediate host-pathogen relationships.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathogen Genomics, Translational Genomics Research Institute, Arizona, United States of America. mchampion@tgen.org

ABSTRACT
Whole genome comparative studies of many bacterial pathogens have shown an overall high similarity of gene content (>95%) between phylogenetically distinct subspecies. In highly clonal species that share the bulk of their genomes subtle changes in gene content and small-scale polymorphisms, especially those that may alter gene expression and protein-protein interactions, are more likely to have a significant effect on the pathogen's biology. In order to better understand molecular attributes that may mediate the adaptation of virulence in infectious bacteria, a comparative study was done to further analyze the evolution of a gene encoding an o-methyltransferase that was previously identified as a candidate virulence factor due to its conservation specifically in highly pathogenic Francisella tularensis subsp. tularensis strains. The o-methyltransferase gene is located in the genomic neighborhood of a known pathogenicity island and predicted site of rearrangement. Distinct o-methyltransferase subtypes are present in different Francisella tularensis subspecies. Related protein families were identified in several host species as well as species of pathogenic bacteria that are otherwise very distant phylogenetically from Francisella, including species of Mycobacterium. A conserved sequence motif profile is present in the mammalian host and pathogen protein sequences, and sites of non-synonymous variation conserved in Francisella subspecies specific o-methyltransferases map proximally to the predicted active site of the orthologous human protein structure. Altogether, evidence suggests a role of the F. t. subsp. tularensis protein in a mechanism of molecular mimicry, similar perhaps to Legionella and Coxiella. These findings therefore provide insights into the evolution of niche-restriction and virulence in Francisella, and have broader implications regarding the molecular mechanisms that mediate host-pathogen relationships.

Show MeSH
Related in: MedlinePlus