title: Human formyl peptide receptor 2 senses highly pathogenic Staphylococcus aureus.
abstract: Virulence of emerging community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and other highly pathogenic S. aureus strains depends on their production of phenol-soluble modulin (PSM) peptide toxins, which combine the capacities to attract and lyse neutrophils. The molecular basis of PSM-stimulated neutrophil recruitment has remained unclear. Here, we demonstrate that the human formyl peptide receptor 2 (FPR2/ALX), which has previously been implicated in control of endogenous inflammatory processes, senses PSMs at nanomolar concentrations and initiates proinflammatory neutrophil responses to CA-MRSA. Specific blocking of FPR2/ALX or deletion of PSM genes in CA-MRSA severely diminished neutrophil detection of CA-MRSA. Furthermore, a specific inhibitor of FPR2/ALX and of its functional mouse counterpart blocked PSM-mediated leukocyte infiltration in vivo in a mouse model. Thus, the innate immune system uses a distinct FPR2/ALX-dependent mechanism to specifically sense bacterial peptide toxins and detect highly virulent bacterial pathogens. FPR2/ALX represents an attractive target for new anti-infective or anti-inflammatory strategies.
authors.affiliation: Cellular and Molecular Microbiology Division, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Elfriede-Aulhorn-Strasse 6, 72076 Tübingen, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kretschmer
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Gleske
authors.forename: Maren
authors.initials: M
authors.lastname: Rautenberg
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Martin
authors.initials: M
authors.lastname: Köberle
authors.forename: Erwin
authors.initials: E
authors.lastname: Bohn
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.forename: Marie-Joséphe
authors.initials: MJ
authors.lastname: Rabiet
authors.forename: Francois
authors.initials: F
authors.lastname: Boulay
authors.forename: Seymour J
authors.initials: SJ
authors.lastname: Klebanoff
authors.forename: Kok A
authors.initials: KA
authors.lastname: van Kessel
authors.forename: Jos A
authors.initials: JA
authors.lastname: van Strijp
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.forename: Andreas
authors.initials: A
authors.lastname: Peschel
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D017714:Community-Acquired Infections / Q000382:microbiology; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000302:isolation & purification / Q000472:pathogenicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D011485:Protein Binding; D044042:Receptors, Formyl Peptide / Q000378:metabolism* / Q000502:physiology; D044067:Receptors, Lipoxin / Q000378:metabolism*; D013203:Staphylococcal Infections
chemical_list: D001427:Bacterial Toxins; C105101:FPR2 protein, human; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C481578:formyl peptide receptor 2, mouse; C025971:staphylococcal delta toxin