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
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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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    • "AMPs may interact with intracellular targets, binding to DNA, RNA and protein, or even interfering with the characterized FtsZ gene, responsible for bacterial cell division septum or with protein synthesis such as DNA gyrase and DnaK (Brogden, 2005; Chauhan et al., 2006; Handler et al., 2008; Maróti et al., 2011). Genetic markers related to the defensins and cathelicidin mediated AMPs resistance include kasB in Mycobacterium marinum (Gao et al., 2003), sak in S. aureus (Jin et al., 2004)—for defensins; and emm1 in Group A Streptococcus (Lauth et al., 2009). Additionally, some AMPs have non-protein targets such as the peptidoglycan precursor lipid II and ATP (Hilpert et al., 2010; Sass et al., 2010). "
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