Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing

The antimicrobial peptide LL-37 is generated upon proteolytic cleavage of cathelicidin and limits invading pathogens by directly targeting microbial membranes as well as stimulating innate immune cell function. However, some microbes evade LL-37-mediated defense. Notably, group A Streptococcus (GAS) strains belonging to the hypervirulent M1T1 serogroup are more resistant to human LL-37 than other GAS serogroups. We show that the GAS surface-associated M1 protein sequesters and neutralizes LL-37 antimicrobial activity through its N-terminal domain. M1 protein also binds the cathelicidin precursor hCAP-18, preventing its proteolytic maturation into antimicrobial forms. Exogenous M1 protein rescues M1-deficient GAS from killing by neutrophils and within neutrophil extracellular traps and neutralizes LL-37 chemotactic properties. M1 also binds murine cathelicidin, and its virulence contribution in a murine model of necrotizing skin infection is largely driven by its ability to neutralize this host defense peptide. Thus, cathelicidin resistance is essential for the pathogenesis of hyperinvasive M1T1 GAS. [Display omitted] •Hypervirulent M1 group A Streptococcus (GAS) resists innate immune clearance•The surface-expressed GAS M1 protein sequesters human cathelicidin LL-37•M1 protein sequestration of immature cathelicidin blocks its activation•The pathogenesis of GAS necrotizing fasciitis requires cathelicidin inhibition A globally disseminated clone of hyperinvasive M1T1 group A Streptococcus (GAS) causes severe infections, including necrotizing fasciitis. LaRock et al. show that M1T1 GAS circumvents immune defenses mediated by human cathelicidin LL-37 by binding this antimicrobial peptide through the bacterial surface protein M1 and sequestering it in a protein trap.