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Significance Regulation of virulence factor production is critical for bacterial pathogenesis. The human pathogen group AStreptococcus (GAS) produces a potent secreted protease, streptococcal pyrogenic exotoxin B (SpeB), that is crucial for pathogenesis. Although it is known that GAS produces SpeB at high population density, the molecular mechanism whereby GAS coordinates temporal SpeB production is unknown. Here, we identify a GAS-encoded short leaderless intercellular peptide signal [SpeB-inducing peptide (SIP)], and define the mechanism by which SIP induces population-wide SpeB production and contributes to GAS virulence. Furthermore, discovery of SIP provides a framework for the identification of SIP-like leaderless peptide signals in other microorganisms. Thus, our data reveal a paradigm of bacterial signaling and identify previously unknown molecules that may serve as therapeutic targets.

Leaderless secreted peptide signaling molecule alters global gene expression and increases virulence of a human bacterial pathogen