DNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection

Most invasive bacterial infections are caused by species that more commonly colonize the human host with minimal symptoms. Although phenotypic or genetic correlates underlying a bacterium's shift to enhanced virulence have been studied, the in vivo selection pressures governing such shifts are poorly understood. The globally disseminated M1T1 clone of group A Streptococcus (GAS) is linked with the rare but life-threatening syndromes of necrotizing fasciitis and toxic shock syndrome 1 . Mutations in the GAS control of virulence regulatory sensor kinase ( covRS ) operon are associated with severe invasive disease, abolishing expression of a broad-spectrum cysteine protease (SpeB) 2 , 3 and allowing the recruitment and activation of host plasminogen on the bacterial surface 4 . Here we describe how bacteriophage-encoded GAS DNase (Sda1), which facilitates the pathogen's escape from neutrophil extracellular traps 5 , 6 , serves as a selective force for covRS mutation. The results provide a paradigm whereby natural selection exerted by the innate immune system generates hypervirulent bacterial variants with increased risk of systemic dissemination.