The group A streptococcus (GAS) is a major bacterial pathogen of humans, globally causing over 700,000,000 infections and more than 500,000 deaths each year. Temperate bacteriophages are prominent genetic elements in GAS with multiple examples found in every published genome and are known to be vectors for virulence genes. However, the effect of phage integration upon host gene expression through promoter inactivation or replacement has not been explored. Our long-term goal is to understand the role of prophages in regulating host gene expression in GAS. The objective of this application is to understand how prophage SF370.4 regulates DNA mismatch repair (MMR) by altering between integrated and episomal forms in response to environmental signals. Our central hypothesis is that prophage SF370.4 acts as genetic regulator of MMR in GAS, protecting rapidly growing cells from unwanted mutations while allowing the accumulation of changes, some of which could be adaptive, when resources become limiting. Once the role of prophages as gene regulators is known, it will aid in devising new pharmacological strategies that may up- or down-regulate GAS genes so as to interfere with normal bacterial metabolism. Further, it may provide key insights into the evolution of new strains of GAS since MMR has been demonstrated to play a key role in controlling horizontal transfer. Therefore, to test our central hypothesis, the specific aims of this application are to: 1) Determine the effect that SF370.4-like prophages have on the mutation rate of their Streptococcus pyogenes hosts, and 2) Identify the contribution to the host mutator phenotype by molecular events associated with prophage SF370.4 integration and excision. A combination of genetic dissection, mutagenesis studies, and microarray analysis will be used to accomplish these goals. The results of these studies are expected to have a positive impact, fundamentally advancing our knowledge of GAS gene regulation and evolution, and thus could lead ultimately to improved control and antimicrobial strategies. Relevance: The group A streptococcus is an important cause of bacterial disease in humans. This research will determine the role of a bacterial virus in regulating a key DNA repair system. The results will increase our understanding of evolution and gene regulation in this bacteria and thus aid in devising new antimicrobial strategies. Significance to Public Health The group A streptococcus is an important cause of bacterial disease in humans. This research will determine the role of a bacterial virus in regulating a key DNA repair system. The results will increase our understanding of evolution and gene regulation in this bacteria and thus aid in devising new antimicrobial strategies. [unreadable] [unreadable] [unreadable]