Natural Variation in the Promoter of the Gene Encoding the Mga Regulator Alters Host-Pathogen Interactions in Group A Streptococcus Carrier Strains

Abstract

ABSTRACTHumans commonly carry pathogenic bacteria asymptomatically, but the molecular factors underlying microbial asymptomatic carriage are poorly understood. We previously reported that two epidemiologically unassociated serotype M3 group AStreptococcus(GAS) carrier strains had an identical 12-bp deletion in the promoter of the gene encoding Mga, a global positive gene regulator. Herein, we report on studies designed to test the hypothesis that the identified 12-bp deletion in themgapromoter alters GAS virulence, thereby potentially contributing to the asymptomatic carrier phenotype. Using allelic exchange, we introduced the variant promoter into a serotype M3 invasive strain and the wild-type promoter into an asymptomatic carrier strain. Compared to strains with the wild-typemgapromoter, we discovered that strains containing the promoter with the 12-bp deletion produced significantly fewermgaand Mga-regulated gene transcripts. Consistent with decreasedmgatranscripts, strains containing the variantmgapromoter were also significantly less virulent inin vivoandex vivomodels of GAS disease. Further, we provide evidence that the pleiotropic regulator protein CodY binds to themgapromoter and that the 12-bp deletion in themgapromoter reduces CodY-mediatedmgatranscription. We conclude that the naturally occurring 12-bp deletion in themgapromoter significantly alters the pathogen-host interaction of these asymptomatic carrier strains. Our findings provide new insight into the molecular basis of the carrier state of an important human pathogen.