A random six-phase switch regulates pneumococcal virulence via global epigenetic changes

• DOI: 10.1038/ncomms6055
• Publication Date: 2014-09-30T14:04:55Z
• Authors: Ana Sousa Manso; Melissa H. Chai; John M. Atack; Leonardo Furi; Megan De Ste Croix; Richard Haigh; Claudia Trappetti; Abiodun D. Ogunniyi; Lucy K. Shewell; Matthew Boitano; Tyson A. Clark; Jonas Korlach; Matthew Blades; Evgeny Mirkes; Alexander N. Gorban; James C. Paton; Michael P. Jennings; Marco R. Oggioni
• Keywords: 570; 572; Molecular Sequence Data; 612; Article; Pneumococcal Infections; Epigenesis, Genetic; Mice; 03 medical and health sciences; Genetic; Bacterial Proteins; Animals; Humans; genetics; DNA Restriction-Modification Enzymes; Inbred BALB C; epigenetic gene regulation; streptococcus pneumoniae; SpnD39III; Mice, Inbred BALB C; 0303 health sciences; epigenetics; Virulence; microbiology; Bacterial; Gene Expression Regulation, Bacterial; 3. Good health; Multidisciplinary Sciences; virulence; Biological sciences; Streptococcus pneumoniae; Gene Expression Regulation; opacity phase variation; gene expression; Female; Microbial genetics; methylation patterns; Epigenesis

AbstractStreptococcus pneumoniae (the pneumococcus) is the world’s foremost bacterial pathogen in both morbidity and mortality. Switching between phenotypic forms (or ‘phases’) that favour asymptomatic carriage or invasive disease was first reported in 1933. Here, we show that the underlying mechanism for such phase variation consists of genetic rearrangements in a Type I restriction-modification system (SpnD39III). The rearrangements generate six alternative specificities with distinct methylation patterns, as defined by single-molecule, real-time (SMRT) methylomics. The SpnD39III variants have distinct gene expression profiles. We demonstrate distinct virulence in experimental infection and in vivo selection for switching between SpnD39III variants. SpnD39III is ubiquitous in pneumococci, indicating an essential role in its biology. Future studies must recognize the potential for switching between these heretofore undetectable, differentiated pneumococcal subpopulations in vitro and in vivo. Similar systems exist in other bacterial genera, indicating the potential for broad exploitation of epigenetic gene regulation.