title: A random six-phase switch regulates pneumococcal virulence via global epigenetic changes.
abstract: Streptococcus 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.
authors.affiliation: 1] Department of Genetics, University of Leicester, Leicester LE1 7RH, UK [2] Dipartimento di Biotechnologie Mediche, Università di Siena, 53100 Siena, Italy.
authors.forename: Ana Sousa
authors.initials: AS
authors.lastname: Manso
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Chai
authors.affiliation: Institute for Glycomics, Griffith University, Southport, Queensland 4215, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Atack
authors.affiliation: 1] Department of Genetics, University of Leicester, Leicester LE1 7RH, UK [2] Dipartimento di Biotechnologie Mediche, Università di Siena, 53100 Siena, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Furi
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: De Ste Croix
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Haigh
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trappetti
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Abiodun D
authors.initials: AD
authors.lastname: Ogunniyi
authors.affiliation: Institute for Glycomics, Griffith University, Southport, Queensland 4215, Australia.
authors.forename: Lucy K
authors.initials: LK
authors.lastname: Shewell
authors.affiliation: Pacific Biosciences, Menlo Park, California 94025, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Boitano
authors.affiliation: Pacific Biosciences, Menlo Park, California 94025, USA.
authors.forename: Tyson A
authors.initials: TA
authors.lastname: Clark
authors.affiliation: Pacific Biosciences, Menlo Park, California 94025, USA.
authors.forename: Jonas
authors.initials: J
authors.lastname: Korlach
authors.affiliation: Bioinformatics and Biostatistics Analysis Support Hub, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Blades
authors.affiliation: Department of Mathematics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Mirkes
authors.affiliation: Department of Mathematics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Gorban
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: 1] Institute for Glycomics, Griffith University, Southport, Queensland 4215, Australia [2].
authors.forename: Michael P
authors.initials: MP
authors.lastname: Jennings
authors.affiliation: 1] Department of Genetics, University of Leicester, Leicester LE1 7RH, UK [2] Dipartimento di Biotechnologie Mediche, Università di Siena, 53100 Siena, Italy [3].
authors.forename: Marco R
authors.initials: MR
authors.lastname: Oggioni
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D015280:DNA Restriction-Modification Enzymes / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011008:Pneumococcal Infections / Q000382:microbiology*; D013296:Streptococcus pneumoniae / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D015280:DNA Restriction-Modification Enzymes