M1 Protein Allows Group A Streptococcal Survival in Phagocyte Extracellular Traps through Cathelicidin Inhibition

Department of Pediatrics, University of California San Diego, La Jolla, Calif. 92093-0687, USA.
Journal of Innate Immunity (Impact Factor: 4.35). 04/2009; 1(3):202-14. DOI: 10.1159/000203645
Source: PubMed


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.

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Available from: Annelies S Zinkernagel, Aug 03, 2014
    • "RESULTS GAS Is Protected by M1 Protein Binding of LL-37 M1T1 GAS lacking M1 protein are more susceptible to killing by human cathelicidin LL-37 (Lauth et al., 2009). M protein is the most abundant protein on the GAS surface (Severin et al., 2007), extending from the bacterial cell surface in the form of hair-like fimbriae (Phillips et al., 1981). "
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    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.
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    • "Functional ClpX was essential for B. anthracis to disrupt host innate immune clearance mechanisms. In a similar manner, the M1 protein from Streptococcus pyogenes was found to contribute to overall resistance of group A Streptococcus to the cathelicidin AMP LL-37 (Lauth et al., 2009). Interestingly , instead of repelling LL-37, the M1 protein was shown to bind and sequester the AMP, thus rendering it harmless against the invading pathogen (Figure 1). "
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    • "Besides entrapment, some pathogens e.g. Escherichia coli and S. pyogenes have been shown to be directly killed within NETs (Brinkmann et al., 2004; Lauth et al., 2009). Other pathogens e.g. "
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