Srv-mediated control of the group A streptococcal multiple gene activator Mga

Group A Streptococcus (GAS) is a Gram-positive human pathogen that encodes a complex regulatory network.  Genomic studies have identified 13 two-component regulatory systems and up to 100 putative stand alone regulators.  Each regulator that has been studied in some detail has been linked to the virulence of the organism.  Among these is the streptococcal regulator of virulence (Srv).  Inactivation of srv results in a significant reduction in virulence in an intraperitoneal murine model and genome wide down regulation in gene transcript levels.  Srv is characterized by a helix-turn-helix (HTH) motif that has been shown to bind DNA and there is evidence to suggest that this DNA binding ability is necessary for Srv function.  To further test this hypothesis, complimentary in vitro and in vivo analyses were used to identify DNA targets that could be directly bound by Srv.  Among the putative targets identified was another transcriptional regulator, Mga.  Srv was shown to bind to the interior coding sequence of mga suggesting an interaction that could result in mga activation or repression.  To test the hypothesis that Mga is a target of Srv-mediated transcriptional control we will use molecular genetics to study mga transcription and subsequent translation in vitro.  Furthermore, we will study the affect of Srv on the production of known targets that are under Mga-mediated control in vitro and in an in vivo model of subcutaneous infection.