title: Receptor-dependent and -independent immunomodulatory effects of phenol-soluble modulin peptides from Staphylococcus aureus on human neutrophils are abrogated through peptide inactivation by reactive oxygen species.
abstract: The virulence and pathogenesis mechanisms of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains depend on a newly described group of phenol-soluble modulin (PSM) peptides (the PSMα peptides) with cytolytic activity. These toxins are α-helical peptides with a formyl group at the N terminus, and they activate neutrophils through formyl peptide receptor 2 (FPR2), a function closely correlated to the capacity of staphylococcal species to cause invasive infections. The effects of two synthetic PSMα peptides were investigated, and we show that they utilize FPR2 and promote neutrophils to produce reactive oxygen species (ROS) which in turn trigger inactivation of the peptides. Independently of FPR2, the PSMα peptides also downregulate the neutrophil response to other stimuli and exert a cytolytic effect to which apoptotic neutrophils are more sensitive than viable cells. The novel immunomodulatory functions of the PSMα peptides were sensitive to ROS generated by the neutrophil myeloperoxidase (MPO)-H(2)O(2) system, suggesting a role for this enzyme system in counteracting bacterial virulence.
authors.affiliation: Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Huamei
authors.initials: H
authors.lastname: Forsman
authors.forename: Karin
authors.initials: K
authors.lastname: Christenson
authors.forename: Johan
authors.initials: J
authors.lastname: Bylund
authors.forename: Claes
authors.initials: C
authors.lastname: Dahlgren
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000378:metabolism* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D009195:Peroxidase / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D013481:Superoxides / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D017382:Reactive Oxygen Species; C025971:staphylococcal delta toxin; D013481:Superoxides; D006861:Hydrogen Peroxide; D009195:Peroxidase; D002118:Calcium