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.
Highlights
Bacterial human pathogens, many of which were at one time treatable with antibiotics, have re-emerged within the last couple of decades as highly infectious public health threats, and in some cases, are potential agents for use as biological weapons
In addition to the growing threat of pan-resistance, most bacterial pathogens are highly infectious and many are transmissible when aerosolized and inhaled by mammalian hosts. These include bacterial pathogens such as Coxiella burnetii, Legionella pneumophila, Mycobacterium tuberculosis, and Francisella tularensis ; all of which cause severely debilitating diseases that can lead to fatality, especially in immunocompromised humans
Francisella tularensis is likely better known for its classification as a potential bacterial biological weapon, a recent report of erythromycin resistance in Francisella tularensis emphasizes the relevance of this organism as a model for studies of adaptive biological processes that enable otherwise mildly infectious environmental bacteria to adapt to specific hosts, and become highly virulent pathogens [1,2]
Summary
Many of which were at one time treatable with antibiotics, have re-emerged within the last couple of decades as highly infectious public health threats, and in some cases, are potential agents for use as biological weapons. Analysis of predicted secondary structures of the subspecies specific o-methyltransferase alleles and comparison to the orthologous human protein structure suggests a functional role for the highly conserved subtype in virulent strains of Francisella.
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