title: M1 protein allows Group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition.
abstract: M1 protein contributes to Group A Streptococcus (GAS) systemic virulence by interfering with phagocytosis and through proinflammatory activities when released from the cell surface. Here we identify a novel role of M1 protein in the stimulation of neutrophil and mast cell extracellular trap formation, yet also subsequent survival of the pathogen within these DNA-based innate defense structures. Targeted mutagenesis and heterologous expression studies demonstrate M1 protein promotes resistance to the human cathelicidin antimicrobial peptide LL-37, an important effector of bacterial killing within such phagocyte extracellular traps. Studies with purified recombinant protein fragments mapped the inhibition of cathelicidin killing to the M1 hypervariable N-terminal domain. A survey of GAS clinical isolates found that strains from patients with necrotizing fasciitis or toxic shock syndrome were significantly more likely to be resistant to cathelicidin than GAS M types not associated with invasive disease; M1 isolates were uniformly resistant. We conclude increased resistance to host cathelicidin and killing within phagocyte extracellular traps contribute to the propensity of M1 GAS strains to produce invasive infections.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, Calif. 92093-0687, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Lauth
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
authors.forename: Case W
authors.initials: CW
authors.lastname: McNamara
authors.forename: Sandra
authors.initials: S
authors.lastname: Myskowski
authors.forename: Annelies S
authors.initials: AS
authors.lastname: Zinkernagel
authors.forename: Bernard
authors.initials: B
authors.lastname: Beall
authors.forename: Partho
authors.initials: P
authors.lastname: Ghosh
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D022082:Cellular Structures / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D004247:DNA / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D019115:Fasciitis, Necrotizing / Q000382:microbiology; D006801:Humans; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000648:ultrastructure*; D011506:Proteins / Q000378:metabolism; D012772:Shock, Septic / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000254:growth & development* / Q000302:isolation & purification / Q000378:metabolism / Q000472:pathogenicity; D054804:Cathelicidins
chemical_list: D000942:Antigens, Bacterial; D023181:Antimicrobial Cationic Peptides; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D011506:Proteins; C014689:streptococcal M protein; D004247:DNA; D054804:Cathelicidins