title: Polyphosphates form antigenic complexes with platelet factor 4 (PF4) and enhance PF4-binding to bacteria.
abstract: Short chain polyphosphates (polyP) are pro-coagulant and pro-inflammatory platelet released inorganic polymers. The platelet chemokine platelet factor 4 (PF4) binds to lipid A on bacteria, inducing an antibody mediated host defense mechanism, which can be misdirected against PF4/heparin complexes leading to the adverse drug reaction heparin-induced thrombocytopenia (HIT). Here, we demonstrate that PF4 complex formation with soluble short chain polyP contributes to host defense mechanisms. Circular dichroism spectroscopy and isothermal titration calorimetry revealed that PF4 changed its structure upon binding to polyP in a similar way as seen in PF4/heparin complexes. Consequently, PF4/polyP complexes exposed neoepitopes to which human anti-PF4/heparin antibodies bound. PolyP enhanced binding of PF4 to Escherichia coli, hereby facilitating bacterial opsonisation and, in the presence of human anti-PF4/polyanion antibodies, phagocytosis. Our study indicates a role of polyP in enhancing PF4-mediated defense mechanisms of innate immunity.
authors.forename: Sven
authors.initials: S
authors.lastname: Brandt
authors.forename: Krystin
authors.initials: K
authors.lastname: Krauel
authors.forename: Miriam
authors.initials: M
authors.lastname: Jaax
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Helm
authors.forename: Sven
authors.initials: S
authors.lastname: Hammerschmidt
authors.affiliation: Mihaela Delcea, PhD, ZIK HIKE - Zentrum für Innovationskompetenz, "Humorale Immunreaktionen bei kardiovaskulären Erkrankungen", Ernst-Moritz-Arndt-Universität Greifswald, Fleischmannstrasse 42-44, 17489 Greifswald, Germany, Tel.: +49 3834 8622343, E-mail: delceam@uni-greifswald.de.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Delcea
authors.affiliation: Prof. Dr. med. Andreas Greinacher, MD, Institut für Immunologie und Transfusionsmedizin, Sauerbruchstrasse, 17475 Greifswald, Germany, Tel.: +49 3834 865482, E-mail: greinach@uni-greifswald.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
mesh_terms: D000941:Antigens / Q000737:chemistry / Q000276:immunology*; D002151:Calorimetry; D002942:Circular Dichroism; D003429:Cross Reactions; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D006493:Heparin / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D009504:Neutrophils / Q000502:physiology; D010587:Phagocytosis; D010978:Platelet Factor 4 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011122:Polyphosphates / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000187:drug effects
chemical_list: D000941:Antigens; D011122:Polyphosphates; D010978:Platelet Factor 4; D006493:Heparin
keywords: Antigen generation; conformational changes; phagocytosis; platelet factor 4; polyphosphates