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Background  Ralp3 is a transcriptional regulator present in a serotype specific fashion on the chromosome of the human pathogen  Streptococcus pyogenes  (group A streptococci, GAS). In serotypes harbouring the  ralp3  gene either positive or negative effects on important metabolic and virulence genes involved in colonization and immune evasion in the human host were observed. A previous study revealed that deletion of  ralp3  in a GAS M49 serotype significantly attenuated many virulence traits and caused metabolic disadvantages. This leads to two questions: (i) which kind of consequences could Ralp3 expression have in GAS serotypes naturally lacking this gene, and (ii) is Ralp3 actively lost during evolution in these serotypes.    Methodology/Principal Findings  We investigated the role of Ralp3 in GAS M2 and M6 pathogenesis. Both serotypes lack  ralp3  on their chromosome. The heterologous expression of  ralp3  in both serotypes resulted in reduced attachment to and internalization into the majority of tested epithelial cells. Both  ralp3  expression strains showed a decreased ability to survive in human blood and exclusively M2:: ralp3  showed decreased survival in human serum. Both mutants secreted more active SpeB in the supernatant, resulting in a higher activity compared to wild type strains. The respective M2 and M6 wild type strains outcompeted the  ralp3  expression strains in direct metabolic competition assays. The phenotypic changes observed in the M2: ralp3  and M6: ralp3  were verified on the transcriptional level. Consistent with the virulence data, tested genes showed transcript level changes in the same direction.    Conclusions/Significance  Together these data suggest that Ralp3 can take over transcriptional control of virulence genes in serotypes lacking the  ralp3  gene. Those serotypes most likely lost Ralp3 during evolution since obviously expression of this gene is disadvantageous for metabolism and pathogenesis.

Heterologous Expression of Ralp3 in Streptococcus pyogenes M2 and M6 Strains Affects the Virulence Characteristics