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.
© 2009 S. Karger AG, Basel
- Group A Streptococcus
- Streptococcus pyogenes
- Virulence factor
- Innate immunity
- M protein
- Mast cell
- Extracellular traps
- Antimicrobial peptide
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Prof. Victor Nizet
Department of Pediatrics and Skaggs School of Pharmacy
and Pharmaceutical Sciences, University of California
9500 Gilman Drive, MC 0687, La Jolla, CA 92093-0687 (USA)
Tel. +1 858 534 7408, Fax +1 858 534 5611, E-Mail email@example.com
X.L. and M.v.K.-B. contributed equally to this manuscript.
Received: November 27, 2008
Accepted after revision: December 15, 2008
Published online: February 20, 2009
Number of Print Pages : 13
Number of Figures : 5, Number of Tables : 0, Number of References : 54
Additional supplemental material is available online.
Journal of Innate Immunity
Vol. 1, No. 3, Year 2009 (Cover Date: April 2009)
Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)
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