M1 Protein Allows Group A Streptococcal Survival in Phagocyte Extracellular Traps through Cathelicidin InhibitionLauth X. · von Köckritz-Blickwede M. · McNamara C.W. · Myskowski S. · Zinkernagel A.S. · Beall B. · Ghosh P. · Gallo R.L. · Nizet V.
Departments of aPediatrics, bChemistry and Biochemistry, and cMedicine, and dSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, Calif., eRespiratory Diseases Branch, Division of Bacterial Diseases, Centers for Disease Control and Prevention, Atlanta, Ga., fVeterans Affairs San Diego Healthcare Center and gRady Children’s Hospital, San Diego, Calif., USA
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.
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)
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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)
For additional information: http://www.karger.com/JIN