Phase variation of DNA methyltransferases and the regulation of virulence and immune evasion in the pathogenic Neisseria

Abstract The pathogenic Neisseria provide textbook examples of phase variation: the high frequency, random and reversible switching of gene expression. Typically, phase variable gene expression is observed in genes required for the expression of surface proteins and carbohydrate structures. All Neisseria gonorrhoeae and N. meningitidis strains also express phase variable DNA methyltransferases that are components of DNA restriction-modification systems. Phase variation of these DNA methyltransferases (Mod) alters global DNA methylation patterns. The change in DNA methylation due to phase variation events alters expression of a regulon of genes, called a phasevarion, and results in differentiation of the population into cells with two distinct phenotypes. For example, in N. meningitidis switching of the modA11 phasevarion alters expression of immunogenic outer membrane proteins such as lactoferrin-binding protein, and also modulates sensitivity to ceftazidime and ciprofloxacin. The modD1 phasevarion is associated with hypervirulent meningococcal clonal complexes. In N. gonorrhoeae, modA13 phasevarion switching generates differentiation into cells that display enhanced biofilm formation and enhanced intracellular survival. Phasevarions are ubiquitous in pathogenic Neisseria and modulate expression of numerous genes. These systems have the potential to impact all studies on vaccine development and pathobiology in the pathogenic Neisseria. Random switching of global gene expression in meningococci and gonococci is mediated by epigenetic regulatory systems called phasevarions.