title: Staphylococcus epidermidis antimicrobial delta-toxin (phenol-soluble modulin-gamma) cooperates with host antimicrobial peptides to kill group A Streptococcus.
abstract: 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 delta-toxin (PSMgamma) is normally present in the epidermis and sparsely in the dermis of human skin using immunohistochemistry. Synthetic delta-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), delta-toxin cooperated with CRAMP, hBD2, and hBD3. In whole blood, addition of delta-toxin exerted a bacteriostatic effect on GAS, and in NETs, delta-toxin increased their killing capacity against this pathogen. Coimmunoprecipitation and tryptophan spectroscopy demonstrated direct binding of delta-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 delta-toxin. Thus, these data suggest that S. epidermidis-derived delta-toxin cooperates with the host-derived antimicrobial peptides in the innate immune system to reduce survival of an important human bacterial pathogen.
authors.affiliation: Division of Dermatology, University of California San Diego, San Diego, California, United States of America.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Cogen
authors.forename: Kenshi
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Jun
authors.initials: J
authors.lastname: Muto
authors.forename: Katheryn M
authors.initials: KM
authors.lastname: Sanchez
authors.forename: Laura
authors.initials: L
authors.lastname: Crotty Alexander
authors.forename: Jackelyn
authors.initials: J
authors.lastname: Tanios
authors.forename: Yuping
authors.initials: Y
authors.lastname: Lai
authors.forename: Judy E
authors.initials: JE
authors.lastname: Kim
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology; D010455:Peptides / Q000494:pharmacology*; D011485:Protein Binding; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013057:Spectrum Analysis / Q000379:methods; D013212:Staphylococcus epidermidis / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D001427:Bacterial Toxins; D010455:Peptides; C025971:staphylococcal delta toxin