Abstract

Many bacterial pathogens contain phase-variable methyltransferases, that control expression of multiple genes. These phase-variable regulons – phasevarions – regulate genes involved in pathogenesis, host-adaptation, and many lead to alteration of antibiotic resistance. Many phasevarions also differentially regulate putative and current vaccine candidates. For vaccines to be effective, they require that their targets are stably expressed. Individual phase-variable genes are able to be identified in silico as they contain easily recognised features. Phasevarions complicate the rational design of vaccines as the genes they regulate do not contain any identifiable features. We have studied a number of systems present in a variety of human and animal pathogens using a number of approaches: PacBio SMRT sequencing and methylome analysis deciphers the methyltransferase specificity of these systems; phenotypic analysis demonstrates global gene expression differences commensurate with methyltransferase switching; a variety of in vivo models shows host niche selection. Our analysis shows that phasevarions are much more widespread than previously thought, and identifies the stably expressed protein repertoire of these bacteria. Our work provides a framework for the rational design of vaccines and treatments against bacterial pathogens containing phasevarions, with this talk summarizing our findings to date.