Abstract
Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, the random switching of the modA gene controls expression of a phase-variable regulon of genes (a “phasevarion”), via differential methylation of the genome in the modA ON and OFF states. Phase-variable mod genes are also present in Neisseria meningitidis and Neisseria gonorrhoeae, suggesting that phasevarions may occur in these important human pathogens. Phylogenetic studies on phase-variable mod genes associated with type III restriction modification (R-M) systems revealed that these organisms have two distinct mod genes—modA and modB. There are also distinct alleles of modA (abundant: modA11, 12, 13; minor: modA4, 15, 18) and modB (modB1, 2). These alleles differ only in their DNA recognition domain. ModA11 was only found in N. meningitidis and modA13 only in N. gonorrhoeae. The recognition site for the modA13 methyltransferase in N. gonorrhoeae strain FA1090 was identified as 5′-AGAAA-3′. Mutant strains lacking the modA11, 12 or 13 genes were made in N. meningitidis and N. gonorrhoeae and their phenotype analyzed in comparison to a corresponding mod ON wild-type strain. Microarray analysis revealed that in all three modA alleles multiple genes were either upregulated or downregulated, some of which were virulence-associated. For example, in N. meningitidis MC58 (modA11), differentially expressed genes included those encoding the candidate vaccine antigens lactoferrin binding proteins A and B. Functional studies using N. gonorrhoeae FA1090 and the clinical isolate O1G1370 confirmed that modA13 ON and OFF strains have distinct phenotypes in antimicrobial resistance, in a primary human cervical epithelial cell model of infection, and in biofilm formation. This study, in conjunction with our previous work in H. influenzae, indicates that phasevarions may be a common strategy used by host-adapted bacterial pathogens to randomly switch between “differentiated” cell types.
Highlights
The pathogenic Neisseria are host-adapted human pathogens that pose a significant health problem worldwide
While phase variation is typically associated with genes encoding surface structures, several hostadapted bacterial pathogens have methyltransferases associated with type III restriction modification (R-M) systems that contain simple tandem DNA repeats that have been proven to phase vary (Pasteurella haemolytica [3], Haemophilus influenzae [4] and Helicobacter pylori [5]) or predicted to phase vary (N. meningitidis, N. gonorrhoeae [6,7], and Moraxella catarrhalis [7]), as reviewed in Fox et al [8]
Rather than affecting the synthesis of a single surface structure, on/off switching of this DNAmethyltransferase gene leads to random switching of multiple genes
Summary
The pathogenic Neisseria are host-adapted human pathogens that pose a significant health problem worldwide. Phase variation is the high frequency reversible on/off switching of gene expression and is commonly mediated by mutations in simple tandem DNA repeats in the open reading frame or promoter region of genes encoding surface expressed virulence determinants [1]. While phase variation is typically associated with genes encoding surface structures, several hostadapted bacterial pathogens have methyltransferases (mod genes) associated with type III restriction modification (R-M) systems that contain simple tandem DNA repeats that have been proven to phase vary (Pasteurella haemolytica [3], Haemophilus influenzae [4] and Helicobacter pylori [5]) or predicted to phase vary (N. meningitidis, N. gonorrhoeae [6,7], and Moraxella catarrhalis [7]), as reviewed in Fox et al [8]
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