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* Eijkman-Winkler Institute, University Medical Center Utrecht, Utrecht, The Netherlands; and
Microbiology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Barcelona, Spain
Bacteria have developed mechanisms to escape the first line of host defense, which is constituted by the recruitment of phagocytes to the sites of bacterial invasion. We previously described the chemotaxis inhibitory protein of Staphylococcus aureus, a protein that blocks the activation of neutrophils via the formyl peptide receptor (FPR) and C5aR. We now describe a new protein from S. aureus that impaired the neutrophil responses to FPR-like1 (FPRL1) agonists. FPRL1 inhibitory protein (FLIPr) inhibited the calcium mobilization in neutrophils stimulated with MMK-1, WKYMVM, prion-protein fragment PrP106–126, and amyloid 
1–42. Stimulation with low concentrations of fMLP was partly inhibited. Directed migration was also completely prevented toward MMK-1 and partly toward fMLP. Fluorescence-labeled FLIPr efficiently bound to neutrophils, monocytes, B cells, and NK cells. HEK293 cells transfected with human C5aR, FPR, FPRL1, and FPRL2 clearly showed that FLIPr directly bound to FPRL1 and, at higher concentrations, also to FPR but not to C5aR and FPRL2. FLIPr can reveal unknown inflammatory ligands crucial during S. aureus infections. As a novel described FPRL1 antagonist, it might lead to the development of therapeutic agents in FPRL1-mediated inflammatory components of diseases such as systemic amyloidosis, Alzheimer’s, and prion disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants "Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (expediente 01/F062)" and "Sociedad Española de Enfermedades Infecciosas y Microbiologia Clinica," (both to C.P.), and by the European Union (LSHM-CT-2004-512093) and the Netherlands Genomics Initiative (050-71-249).
2 Address correspondence and reprint requests to Dr. Kok P. M. van Kessel, Eijkman-Winkler Institute, University Medical Center Utrecht, G04.614, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail address: k.kessel{at}umcutrecht.nl
3 Abbreviations used in this paper: LTB4, leukotriene B4; PAF, platelet-activating factor; CHIPS, chemotaxis inhibitory protein of S. aureus; FPR, formyl peptide receptor; FPRL, FPR-like receptor; A, amyloid ; FLIPr, FPRL1 inhibitory protein; HA, hemagglutinin; PMN, polymorphonuclear neutrophil; HSA, human serum albumin; HEK, human embryonic kidney; GRO, growth-related oncogene; MPO, myeloperoxidase.
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