title: Emergence of a New Highly Successful Acapsular Group A Streptococcus Clade of Genotype emm89 in the United Kingdom.
abstract: Group A Streptococcus (GAS) genotype emm89 is increasingly recognized as a leading cause of disease worldwide, yet factors that underlie the success of this emm type are unknown. Surveillance identified a sustained nationwide increase in emm89 invasive GAS disease in the United Kingdom, prompting longitudinal investigation of this genotype. Whole-genome sequencing revealed a recent dramatic shift in the emm89 population with the emergence of a new clade that increased to dominance over previous emm89 variants. Temporal analysis indicated that the clade arose in the early 1990s but abruptly increased in prevalence in 2008, coinciding with an increased incidence of emm89 infections. Although standard variable typing regions (emm subtype, tee type, sof type, and multilocus sequence typing [MLST]) remained unchanged, uniquely the emergent clade had undergone six distinct regions of homologous recombination across the genome compared to the rest of the sequenced emm89 population. Two of these regions affected known virulence factors, the hyaluronic acid capsule and the toxins NADase and streptolysin O. Unexpectedly, and in contrast to the rest of the sequenced emm89 population, the emergent clade-associated strains were genetically acapsular, rendering them unable to produce the hyaluronic acid capsule. The emergent clade-associated strains had also acquired an NADase/streptolysin O locus nearly identical to that found in emm12 and modern emm1 strains but different from the rest of the sequenced emm89 population. The emergent clade-associated strains had enhanced expression of NADase and streptolysin O. The genome remodeling in the new clade variant and the resultant altered phenotype appear to have conferred a selective advantage over other emm89 variants and may explain the changes observed in emm89 GAS epidemiology.
  
  
  OBJECTIVE
  Sudden upsurges or epidemic waves are common features of group A streptococcal disease. Although the mechanisms behind such changes are largely unknown, they are often associated with an expansion of a single genotype within the population. Using whole-genome sequencing, we investigated a nationwide increase in invasive disease caused by the genotype emm89 in the United Kingdom. We identified a new clade variant that had recently emerged in the emm89 population after having undergone several core genomic recombination-related changes, two of which affected known virulence factors. An unusual finding of the new variant was the loss of the hyaluronic acid capsule, previously thought to be essential for causing invasive disease. A further genomic adaptation in the NADase/streptolysin O locus resulted in enhanced production of these toxins. Recombination-related genome remodeling is clearly an important mechanism in group A Streptococcus that can give rise to more successful and potentially more pathogenic variants.
authors.affiliation: Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London, United Kingdom claire.turner01@imperial.ac.uk s.sriskandan@imperial.ac.uk.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Turner
authors.affiliation: Bioinformatics Support Service, Department of Life Sciences, Imperial College London, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Abbott
authors.affiliation: Public Health England, London, United Kingdom.
authors.forename: Theresa
authors.initials: T
authors.lastname: Lamagni
authors.affiliation: Pathogen Genomics, The Wellcome Trust Sanger Institute, Cambridge, United Kingdom School of Medicine, University of St. Andrews, St. Andrews, United Kingdom.
authors.forename: Matthew T G
authors.initials: MT
authors.lastname: Holden
authors.affiliation: Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Sophia
authors.initials: S
authors.lastname: David
authors.affiliation: Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London, United Kingdom MRC Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jones
authors.affiliation: MRC Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom.
authors.forename: Laurence
authors.initials: L
authors.lastname: Game
authors.affiliation: Public Health England, London, United Kingdom.
authors.forename: Androulla
authors.initials: A
authors.lastname: Efstratiou
authors.affiliation: Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London, United Kingdom claire.turner01@imperial.ac.uk s.sriskandan@imperial.ac.uk.
authors.forename: Shiranee
authors.initials: S
authors.lastname: Sriskandan
mesh_terms: D016667:Bacterial Capsules / Q000235:genetics*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D001427:Bacterial Toxins / Q000235:genetics; D002876:Chromosomes, Bacterial; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D062665:Epidemiological Monitoring; D015870:Gene Expression; D005838:Genotype; D059765:Homologous Recombination; D006801:Humans; D008137:Longitudinal Studies; D017720:Molecular Epidemiology; D008969:Molecular Sequence Data; D058889:Molecular Typing; D009244:NAD+ Nucleosidase / Q000096:biosynthesis / Q000235:genetics; D015995:Prevalence; D017422:Sequence Analysis, DNA; D013290:Streptococcal Infections / Q000453:epidemiology* / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification*; D013301:Streptolysins / Q000096:biosynthesis / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology; D037521:Virulence Factors / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004269:DNA, Bacterial; D013301:Streptolysins; D037521:Virulence Factors; C025964:streptolysin O; D009244:NAD+ Nucleosidase