Analysis of the role of CovR and CovS in the dissemination of Streptococcus pyogenes in invasive skin disease.

The global regulatory two-component system CovR/S controls expression of about 15% of the Streptococcus pyogenes (group A streptococcus; GAS) genome. Recently, we found that CovS plays a pivotal role in general stress response of this strictly human pathogen. Therefore, we expected that both CovS and CovR might affect virulence. In this work, mice were inoculated subcutaneously with isogenic nonpolar covR and covS deletion-substitution mutants and the isogenic wild-type strain. The covS mutant behaved like the wild-type parental strain in terms of resulting lesion appearance and invasive disease leading to death. This is in agreement with previous results suggesting that the absence of its cognate sensor kinase does not affect the ability of CovR to become phosphorylated and cause repression of its regulon. However, two different covR deletion-substitution mutants caused significantly less invasive disease and death in the mice than the wild-type parental strain, although the local lesions produced by the covR mutants were more severe and purulent than those resulting from the wild-type GAS strain. Thus, it appears that production of CovR increases the ability of S. pyogenes to cause severe invasive disease in this mouse model and therefore is an important virulence factor for this organism.