Staphylococcus epidermidis Antimicrobial d-Toxin (Phenol-Soluble Modulin-c) Cooperates with Host Antimicrobial Peptides to Kill Group A Streptococcus

Antimicrobial peptides play an important role in host defense against pathogens. Recently, phenol-soluble modulins (PSMs) from Staphylococcus epidermidis (S. epidermidis) were shown to interact with lipid membranes, form complexes, and exert antimicrobial activity. Based on the abundance and innocuity of the cutaneous resident S. epidermidis, we hypothesized that their PSMs contribute to host defense. Here we show that S. epidermidis d-toxin (PSMc) is normally present in the epidermis and sparsely in the dermis of human skin using immunohistochemistry. Synthetic d-toxin interacted with neutrophil extracellular traps (NETs) and colocalized with cathelicidin while also inducing NET formation in human neutrophils. In antimicrobial assays against Group A Streptococcus (GAS), d-toxin cooperated with CRAMP, hBD2, and hBD3. In whole blood, addition of d-toxin exerted a bacteriostatic effect on GAS, and in NETs, d-toxin increased their killing capacity against this pathogen. Coimmunoprecipitation and tryptophan spectroscopy demonstrated direct binding of d-toxin to host antimicrobial peptides LL-37, CRAMP, hBD2, and hBD3. Finally, in a mouse wound model, GAS survival was reduced (along with Mip-2 cytokine levels) when the wounds were pretreated with d-toxin. Thus, these data suggest that S. epidermidis–derived d-toxin cooperates with the host-derived antimicrobial peptides in the innate immune system to reduce survival of an important human bacterial pathogen. Citation: Cogen AL, Yamasaki K, Muto J, Sanchez KM, Crotty Alexander L, et al. (2010) Staphylococcus epidermidis Antimicrobial d-Toxin (Phenol-Soluble Modulin-c) Cooperates with Host Antimicrobial Peptides to Kill Group A Streptococcus. PLoS ONE 5(1): e8557. doi:10.1371/journal.pone.0008557 Editor: Frank R. DeLeo, National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States of America Received September 2, 2009; Accepted December 10, 2009; Published January 5, 2010 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: This work was supported by National Institutes of Health grants P01HL057345, R56AI083358, and R01AR45676, and a VA Merit award (RLG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]