Dissection of the Molecular Basis for Hypervirulence of an In Vivo—Selected Phenotype of the Widely Disseminated M1T1 Strain of Group A Streptococcus Bacteria

Group A streptococci (GAS) may engage different sets of virulence strategies, depending on the site of infection and host context. We previously isolated 2 phenotypic variants of a globally disseminated M1T1 GAS clone: a virulent wild-type (WT) strain, characterized by a SpeB + /SpeA − /Sda1 low phenotype, and a hypervirulent animal-passaged (AP) strain, better adapted to survive in vivo, with a SpeB + /SpeA − /Sda1 high phenotype. This AP strain arises in vivo due to the selection of bacteria with mutations in covS, the sensor part of a key 2- component regulatory system, CovR/S. To determine whether covS mutations explain the hypervirulence of the AP strain, we deleted covS from WT bacteria (ΔCovS) and were able to simulate the hypervirulence and gene expression phenotype of naturally selected AP bacteria. Correction of the covS mutation in AP bacteria reverted them back to the WT phenotype. Our data confirm that covS plays a direct role in regulating GAS virulence.