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

  • Author(s): LaRock, Christopher N
  • Döhrmann, Simon
  • Todd, Jordan
  • Corriden, Ross
  • Olson, Joshua
  • Johannssen, Timo
  • Lepenies, Bernd
  • Gallo, Richard L
  • Ghosh, Partho
  • Nizet, Victor
  • et al.
Abstract

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.

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