A phasevarion controls multiple virulence traits, including expression of vaccine candidates, in Streptococcus pneumoniae

Abstract

Streptococcus pneumoniae is the most common cause of bacterial illness worldwide. Current vaccines based on the polysaccharide capsule (PCV-13 and PPSV-23) are only effective against a limited number of the >100 capsular serotypes. A universal vaccine based on conserved protein antigens requires a thorough understanding of gene expression in S. pneumoniae. Restriction-Modification (R-M) systems, classically described as a defence against bacteriophage, are almost ubiquitous in the bacterial domain, and roles other than phage defence. All S. pneumoniae strains encode the SpnIII R-M system. This system contains a phase-variable methyltransferase that randomly switches specificity, and controls expression of multiple genes; a phasevarion. We aimed to determine the role of the SpnIII phasevarion during pneumococcal pathobiology and determine if phase-variation resulted in differences in expression of protein antigens that are being investigated as vaccine candidates. Using 'locked' S. pneumoniae strains that express a single SpnIII methyltransferase specificity, we found significant differences in clinically relevant traits, including survival in blood, and adherence to and invasion of human cells. Crucially, we also observed differences in expression of numerous proteinaceous vaccine candidates, which complicates selection of protein antigens for inclusion in a universal protein-based pneumococcal vaccine. This study will inform future vaccine design against S. pneumoniae by ensuring only stably expressed candidates are included in a rationally designed vaccine.

The streptococcal phase-variable Type I Restriction-Modification system SsuCC20p dictates the methylome ofStreptococcus suisand impacts virulence

“…Epigenetic regulation of bacterial gene expression by phase-variable RM systems plays an important role in host-microbe interactions, including bacterial pathogenesis (7,13,(30)(31)(32)(33).…”

“…In contrast to previously characterized phase-variable Type I RM systems, we demonstrate that additional hsdS alleles further downstream of hsdM are not always silent. To the best of our knowledge, in all phase-variable Type I RM systems described so far, only the hsdS allele directly downstream of the hsdM is transcribed and involved in genome methylation (10,13,26,27,30,31,34). Therefore, it was suggested that the other TRDs or hsdS within the locus are merely present to function as DNA templates for recombination (34).…”