A uniquely human sebum lipid drives streptococcal skin infection severity

Free fatty acids (FAs) secreted by the sebaceous glands are critical components of the skin barrier. Here, we investigate the activity of the major FA species present in the skin against Streptococcus pyogenes (group A Streptococcus [GAS]), a major cause of skin infections, such as impetigo, erysipelas, cellulitis, and necrotizing fasciitis. Several relevant FAs had antimicrobial activity against GAS, and linoleic acid was found to be therapeutic when applied in a murine skin infection model. However, sapienic acid, a FA abundant only in human sebum, significantly worsened disease severity despite possessing antimicrobial activity. Transcriptional profiling and molecular genetic analysis showed that sapienic acid, but not other structurally similar FAs, induced the sag operon. The sag operon encodes streptolysin S (SLS), and sapienic acid induction of this cytolytic toxin significantly increased hemolysis of human red blood cells by GAS. Screening of additional FAs identified forms with combined antimicrobial and anti-lytic activity useful as therapeutics. Taken together, we report a species- and tissue-specific trigger for GAS virulence and limitations to the use of FAs as therapeutics against infectious disease.IMPORTANCEGAS naturally only infects humans. Here, we report that the human-specific sebum lipid sapienic acid induces production of streptolysin S (SLS), the hemolysin responsible for the hallmark β-hemolytic phenotype of GAS. Reliance on detection of a human-specific FA for expression of a critical virulence factor exposes a vulnerability of GAS and suggests a potentially variable role for SLS at different infection sites. Furthermore, it details a limitation of existing infection models, which all lack sapienic acid, for understanding the role of SLS in disease.