M1 protein allows Group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition.
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.
Lauth
Xavier
X
Department of Pediatrics, University of California San Diego, La Jolla, Calif. 92093-0687, USA.
von Köckritz-Blickwede
Maren
M
McNamara
Case W
CW
Myskowski
Sandra
S
Zinkernagel
Annelies S
AS
Beall
Bernard
B
Ghosh
Partho
P
Gallo
Richard L
RL
Nizet
Victor
V
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
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