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Letter

Nature Medicine 13, 981 - 985 (2007)
Published online: 15 July 2007 | doi:10.1038/nm1612

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

Mark J Walker1, Andrew Hollands1, Martina L Sanderson-Smith1, Jason N Cole1, Joshua K Kirk1, Anna Henningham1, Jason D McArthur1, Katrin Dinkla2, Ramy K Aziz3,4, Rita G Kansal4,5, Amelia J Simpson6, John T Buchanan6, Gursharan S Chhatwal2, Malak Kotb4,5 & Victor Nizet6,7

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 syndrome1. 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 surface4. Here we describe how bacteriophage-encoded GAS DNase (Sda1), which facilitates the pathogen's escape from neutrophil extracellular traps5, 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.