title: Staphylococcus aureus formyl peptide receptor-like 1 inhibitor (FLIPr) and its homologue FLIPr-like are potent FcγR antagonists that inhibit IgG-mediated effector functions.
abstract: To evade opsonophagocytosis, Staphylococcus aureus secretes various immunomodulatory molecules that interfere with effective opsonization by complement and/or IgG. Immune-evasion molecules targeting the phagocyte receptors for these opsonins have not been described. In this study, we demonstrate that S. aureus escapes from FcγR-mediated immunity by secreting a potent FcγR antagonist, FLIPr, or its homolog FLIPr-like. Both proteins were previously reported to function as formyl peptide receptor inhibitors. Binding of FLIPr was mainly restricted to FcγRII receptors, whereas FLIPr-like bound to different FcγR subclasses, and both competitively blocked IgG-ligand binding. They fully inhibited FcγR-mediated effector functions, including opsonophagocytosis and subsequent intracellular killing of S. aureus by neutrophils and Ab-dependent cellular cytotoxicity of tumor cells by both neutrophils and NK cells. In vivo, treatment of mice with FLIPr-like prevented the development of an immune complex-mediated FcγR-dependent Arthus reaction. This study reveals a novel immune-escape function for S. aureus-secreted proteins that may lead to the development of new therapeutic agents in FcγR-mediated diseases.
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Stemerding
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Pandey
authors.forename: Annemarie
authors.initials: A
authors.lastname: Kuipers
authors.forename: Jeanette H
authors.initials: JH
authors.lastname: Leusen
authors.forename: Peter
authors.initials: P
authors.lastname: Boross
authors.forename: Maaike
authors.initials: M
authors.lastname: Nederend
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
authors.forename: Annemarie Y L
authors.initials: AY
authors.lastname: Weersink
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Kok P M
authors.initials: KP
authors.lastname: van Kessel
authors.forename: Jos A G
authors.initials: JA
authors.lastname: van Strijp
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D001666:Binding Sites, Antibody / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000276:immunology; D007941:Leukemia P388 / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity
chemical_list: D001426:Bacterial Proteins; C516018:FPRL1 inhibitory protein, S aureus; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; C493134:chemotaxis inhibitory protein, Staphylococcus aureus