Molecular characterization of covRS mutations in M1UK Streptococcus pyogenes
Abstract
Increasingly invasive Streptococcus pyogenes disease has been linked to the emergence of the M1UK lineage. Here, we used a murine infection model to investigate the ability of M1UK to accumulate mutations in the covRS operon which regulates up to 15% of the genome, including multiple virulence factors. Assessing an M1UK isolate carrying an Ala111Val nonsynonymous mutation showed that in vitro, M1UK CovRAla111Val was characterized by decreased SpeB expression, increased streptolysin O and hyaluronic acid capsule expression, and resistance to neutrophil killing. While Ala111Val represents a minor biochemical change, we show that CovRAla111Val prevents phosphorylation-dependent dimerization. Specifically, molecular dynamics simulations suggest CovRAla111Val destabilizes the interface between CovR monomers that facilitate dimerization, likely inhibiting CovR dimer-mediated transcriptional repression and promoting altered virulence factor expression. Ultimately, this work underscores the need for ongoing epidemiological surveillance to monitor the emergence of such mutations within the already hypervirulent M1UK lineage.
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