title: M-protein and other intrinsic virulence factors of Streptococcus pyogenes are encoded on an ancient pathogenicity island.
abstract: BACKGROUND
  The increasing number of completely sequenced bacterial genomes allows comparing their architecture and genetic makeup. Such new information highlights the crucial role of lateral genetic exchanges in bacterial evolution and speciation.
  
  
  RESULTS
  Here we analyzed the twelve sequenced genomes of Streptococcus pyogenes by a naïve approach that examines the preferential nucleotide usage along the chromosome, namely the usage of G versus C (GC-skew) and T versus A (TA-skew). The cumulative GC-skew plot presented an inverted V-shape composed of two symmetrical linear segments, where the minimum and maximum corresponded to the origin and terminus of DNA replication. In contrast, the cumulative TA-skew presented a V-shape, which segments were interrupted by several steep slopes regions (SSRs), indicative of a different nucleotide composition bias. Each S. pyogenes genome contained up to nine individual SSRs, encompassing all described strain-specific prophages. In addition, each genome contained a similar unique non-phage SSR, the core of which consisted of 31 highly homologous genes. This core includes the M-protein, other mga-related factors and other virulence genes, totaling ten intrinsic virulence genes. In addition to a high content in virulence-related genes and to a peculiar nucleotide bias, this SSR, which is 47 kb-long in a M1GAS strain, harbors direct repeats and a tRNA gene, suggesting a mobile element. Moreover, its complete absence in a M-protein negative group A Streptococcus natural isolate demonstrates that it could be spontaneously lost, but in vitro deletion experiments indicates that its excision occurred at very low rate. The stability of this SSR, combined to its presence in all sequenced S. pyogenes sequenced genome, suggests that it results from an ancient acquisition.
  
  
  CONCLUSIONS
  Thus, this non-phagic SSR is compatible with a pathogenicity island, acquired before S. pyogenes speciation. Its potential excision might bear relevance for vaccine development, because vaccines targeting M-protein might select for M-protein-negative variants that still carry other virulence determinants.
authors.affiliation: Department of Fundamental Microbiology, University of Lausanne, Quartier UNIL-Sorge, Bâtiment Biophore, Lausanne, Switzerland. panchaud@u.washington.edu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Panchaud
authors.forename: Lionel
authors.initials: L
authors.lastname: Guy
authors.forename: François
authors.initials: F
authors.lastname: Collyn
authors.forename: Marisa
authors.initials: M
authors.lastname: Haenni
authors.forename: Masanobu
authors.initials: M
authors.lastname: Nakata
authors.forename: Andreas
authors.initials: A
authors.lastname: Podbielski
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreillon
authors.forename: Claude-Alain H
authors.initials: CA
authors.lastname: Roten
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics*; D001482:Base Composition; D002352:Carrier Proteins / Q000235:genetics*; D002872:Chromosome Deletion; D002876:Chromosomes, Bacterial / Q000235:genetics; D049810:Genetic Speciation; D016680:Genome, Bacterial; D044404:Genomic Islands / Q000235:genetics*; D023281:Genomics / Q000379:methods; D013045:Species Specificity; D013297:Streptococcus pyogenes / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D037521:Virulence Factors; C014689:streptococcal M protein