title: Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing.
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.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: LaRock
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Döhrmann
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Todd
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Corriden
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany; Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Johannssen
authors.affiliation: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany; Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany; Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Partho
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: vnizet@ucsd.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D057131:Immune Evasion; D051379:Mice; D011485:Protein Binding; D017192:Skin Diseases, Bacterial / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000382:microbiology / Q000473:pathology; D013297:Streptococcus pyogenes / Q000276:immunology* / Q000378:metabolism*; D054804:Cathelicidins
chemical_list: D000942:Antigens, Bacterial; D023181:Antimicrobial Cationic Peptides; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; C014689:streptococcal M protein; D054804:Cathelicidins