A protease-sensing circuit links neutrophil inflammation to virulence regulation in Streptococcus pyogenes

Streptococcus pyogenes (Group A Streptococcus) causes infections with a disproportionately hyperinflammatory response from the host, such as scarlet fever, necrotizing fasciitis, and toxic shock syndrome. Inflammation is specifically driven by S. pyogenes virulence factors, including the protease SpeB, but how inflammation impacts SpeB expression in return during disease is unknown. In this study, we identify a novel interaction between NETosis, a form of inflammatory cell death for neutrophils, and the induction of speB. Specifically, while the cathelicidin peptide LL-37 can repress speB through the two-component regulatory system CovRS, neutrophil proteases released during NETosis relieve repression of speB by degrading another repressor of speB, the bacterial protein Vfr. Furthermore, at high cell densities, SpeB autoregulates its expression through similar degradation of Vfr. Abrogating the formation of NETs or depleting neutrophils resulted in speB repression in vivo, showing the mutual host and pathogen counterattacks collectively lead to the pathological exacerbations characteristic of disease.