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Role of Vpma phase variation in Mycoplasma agalactiae pathogenesis.

ABSTRACT: Compared with other bacterial pathogens, the molecular mechanisms of mycoplasma pathogenicity are largely unknown. Several studies in the past have shown that pathogenic mycoplasmas are equipped with sophisticated genetic systems that allow them to undergo high-frequency surface antigenic variations. Although never clearly proven, these variable mycoplasma surface components are often implicated in host immune evasion and adaptation. Vpma surface lipoproteins of the ruminant pathogen Mycoplasma agalactiae are encoded on a genomic pathogenicity island-like locus and are considered as one of the well-characterized model systems of mycoplasma surface antigenic variation. The present study assesses the role of these phase-variable Vpmas in the molecular pathogenesis of M. agalactiae by testing the wild-type strain PG2 in comparison with the xer1-disrupted Vpma 'phase-locked' mutants in sheep infection models. The data clearly illustrate that although Xer1 recombinase is not a virulence factor of M. agalactiae and Vpma phase variation is not necessary for establishing an infection, it might critically influence the survival and persistence of the pathogen under natural field conditions, mainly due to a better capacity for dissemination and evoking systemic responses. This is the first study where mycoplasma 'phase-locked' mutants are tested in vivo to elucidate the role of phase variation during infection.

SUBMITTER: Chopra-Dewasthaly R

PROVIDER: S-EPMC4510919 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Role of Vpma phase variation in Mycoplasma agalactiae pathogenesis.

Chopra-Dewasthaly Rohini R Baumgartner Martina M Gamper Erika E Innerebner Carmen C Zimmermann Martina M Schilcher Franz F Tichy Alexander A Winter Petra P Jechlinger Wolfgang W Rosengarten Renate R Spergser Joachim J

FEMS immunology and medical microbiology 20120821 3

Compared with other bacterial pathogens, the molecular mechanisms of mycoplasma pathogenicity are largely unknown. Several studies in the past have shown that pathogenic mycoplasmas are equipped with sophisticated genetic systems that allow them to undergo high-frequency surface antigenic variations. Although never clearly proven, these variable mycoplasma surface components are often implicated in host immune evasion and adaptation. Vpma surface lipoproteins of the ruminant pathogen Mycoplasma ...[more]

PMID: 22809092

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Project description:Despite very small genomes, mycoplasmas retain large multigene families encoding variable antigens whose exact role in pathogenesis needs to be proven. To understand their in vivo significance, we used Mycoplasma agalactiae as a model exhibiting high-frequency variations of a family of immunodominant Vpma lipoproteins via Xer1-mediated site-specific recombinations. Phase-Locked Mutants (PLMs) expressing single stable Vpma products served as first breakthrough tools in mycoplasmology to study the role of such sophisticated antigenic variation systems. Comparing the general clinical features of sheep infected with a mixture of phase-invariable PLMs (PLMU and PLMY) and the wild type strain, it was earlier concluded that Vpma phase variation is not necessary for infection. Conversely, the current study demonstrates the in vivo indispensability of Vpma switching as inferred from the Vpma phenotypic and genotypic analyses of reisolates obtained during sheep infection and necropsy. PLMY and PLMU stably expressing VpmaY and VpmaU, respectively, for numerous in vitro generations, switched to new Vpma phenotypes inside the sheep. Molecular genetic analysis of selected 'switchover' clones confirmed xer1 disruption and revealed complex new rearrangements like chimeras, deletions and duplications in the vpma loci that were previously unknown in type strain PG2. Another novel finding is the differential infection potential of Vpma variants, as local infection sites demonstrated an almost complete dominance of PLMY over PLMU especially during early stages of both conjunctival and intramammary co-challenge infections, indicating a comparatively better in vivo fitness of VpmaY expressors. The data suggest that Vpma antigenic variation is imperative for survival and persistence inside the immunocompetent host, and although Xer1 is necessary for causing Vpma variation in vitro, it is not a virulence factor because alternative Xer1-independent mechanisms operate in vivo, likely under the selection pressure of the host-induced immune response. This singular study highlights exciting new aspects of mycoplasma antigenic variation systems, including the regulation of expression by host factors.

Project description:UnlabelledMycoplasmas are minimal, wall-less bacteria but have retained the ability to secrete complex carbohydrate polymers that constitute a glycocalyx. In members of the Mycoplasma mycoides cluster, which are important ruminant pathogens, the glycocalyx includes both cell-attached and cell-free polysaccharides. This report explores the potential secretion of polysaccharides by M. agalactiae, another ruminant pathogen that belongs to a distant phylogenetic group. Comparative genomic analyses showed that M. agalactiae possesses all the genes required for polysaccharide secretion. Notably, a putative synthase gene (gsmA) was identified, by in silico reconstruction of the biosynthetic pathway, that could be involved in both polymerization and export of the carbohydrate polymers. M. agalactiae polysaccharides were then purified in vitro and found to be mainly cell attached, with a linear β-(1→6)-glucopyranose structure [β-(1→6)-glucan]. Secretion of β-(1→6)-glucan was further shown to rely on the presence of a functional gsmA gene, whose expression is subjected to high-frequency phase variation. This event is governed by the spontaneous intraclonal variation in length of a poly(G) tract located in the gsmA coding sequence and was shown to occur in most of the M. agalactiae clinical isolates tested in this study. M. agalactiae susceptibility to serum-killing activity appeared to be dictated by ON/OFF switching of β-(1→6)-glucan secretion, suggesting a role of this phenomenon in survival of the pathogen when it invades the host bloodstream. Finally, β-(1→6)-glucan secretion was not restricted to M. agalactiae but was detected also in M. mycoides subsp. capri PG3(T), another pathogen of small ruminants.ImportanceMany if not all bacteria are able to secrete polysaccharides, either attached to the cell surface or exported unbound into the extracellular environment. Both types of polysaccharides can play a role in bacterium-host interactions. Mycoplasmas are no exception despite their poor overall metabolic capacity. We showed here that M. agalactiae secretes a capsular β-(1→6)-glucopyranose thanks to a specific glycosyltransferase with synthase activity. This secretion is governed by high-frequency ON/OFF phase variation that might be crucial in mycoplasma host dissemination, as cell-attached β-(1→6)-glucopyranose increases serum-killing susceptibility. Our results provide functional genetic data about mycoplasmal glycosyltransferases with dual functions, i.e., assembly and export of the sugar polymers across the cell membrane. Furthermore, we demonstrated that nonprotein epitopes can be subjected to surface antigenic variation in mycoplasmas. Finally, the present report contributes to unravel the role of secreted polysaccharides in the virulence and pathogenicity of these peculiar bacteria.

Dataset Information

Role of Vpma phase variation in Mycoplasma agalactiae pathogenesis.

Publications

Role of Vpma phase variation in Mycoplasma agalactiae pathogenesis.

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