Researchers found that a single change in a bacterial sensor protein (CovS Y39H) makes a normally harmless throat strain of Strep pyogenes less dangerous and less able to react to the antimicrobial peptide LL‑37, which normally signals the bacteria to turn on its virulence genes.

Streptococcus pyogenes, also known as group A Streptococcus, causes a wide variety of diseases ranging from mild noninvasive to severe invasive infections. To identify possible causes of colonization-to-invasive switches, we determined the genomic sequences of 10 isolates from five pairs each composed of an invasive strain and a carriage strain originating from five infectious clusters. Among them, one pair displayed a single-nucleotide difference in <i>covS</i>, encoding the sensor histidine kinase of the two-component CovRS system that controls the expression of 15% of the genome. In contrast to previously described cases where the invasive strains harbor nonfunctional CovS proteins, the carriage strain possessed the mutation <i>covST115C</i>, leading to the replacement of the tyrosine at position 39 by a histidine. The CovSY39H mutation affected the expression of the genes from the CovR regulon in a unique fashion. Genes usually overexpressed in <i>covS</i> mutant strains were underexpressed and vice versa. Furthermore, the <i>covS</i> mutant strain barely responded to the addition of the CovS-signaling compounds Mg²⁺ and LL-37. The variations in the accumulation of two virulence factors paralleled the transcription modifications. In addition, the <i>covST115C</i> mutant strain showed less survival than its wild-type counterpart in murine macrophages. Finally, in two murine models of infection, the <i>covS</i> mutant strain was less virulent than the wild-type strain. Our study suggests that the CovSY39H protein compromises CovS phosphatase activity and that this yields a noninvasive strain. <b>IMPORTANCE</b> Streptococcus pyogenes, also known as group A Streptococcus, causes a wide variety of diseases, leading to 517,000 deaths yearly. The two-component CovRS system, which responds to MgCl₂ and the antimicrobial peptide LL-37, controls the expression of 15% of the genome. Invasive strains may harbor nonfunctional CovS sensor proteins that lead to the derepression of most virulence genes. We isolated a colonization strain that harbors a novel <i>covS</i> mutation. This mutant strain harbored a transcriptome profile opposite that of other <i>covS</i> mutant strains, barely responded to environmental signals, and was less virulent than the wild-type strain. This supports the importance of the derepression of the expression of most virulence genes, via mutations that impact the phosphorylation of the regulator CovR, for favoring S. pyogenes invasive infections.