title: Fibronectin-binding proteins of Staphylococcus aureus mediate activation of human platelets via fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG binding to the FcgammaRIIa receptor.
abstract: Staphylococcus aureus is a leading cause of infective endocarditis (IE). Platelet activation promoted by S. aureus resulting in aggregation and thrombus formation is an important step in the pathogenesis of IE. Here, we report that the fibrinogen/fibronectin-binding proteins FnBPA and FnBPB are major platelet-activating factors on the surface of S. aureus from the exponential phase of growth. Truncated derivatives of FnBPA, presenting either the fibrinogen-binding A domain or the fibronectin-binding BCD region, each promoted platelet activation when expressed on the surface of S. aureus or Lactococcus lactis, indicating two distinct mechanisms of activation. FnBPA-promoted platelet activation is mediated by fibrinogen and fibronectin bridges between the A domain and the BCD domains, respectively, to the low affinity form of the integrin GPIIb/IIIa on resting platelets. Antibodies recognizing the FnBPA A domain or the complex between the FnBPA BCD domains and fibronectin were essential for activation promoted by bacteria expressing the A domain or the BCD domain respectively. Activation was inhibited by a monoclonal antibody (IV-3) specific for the FcgammaRIIa IgG receptor on platelets. We propose that the activation of quiescent platelets by bacteria expressing FnBPs involves the formation of a bridge between the bacterial cell and the platelet surface by (i) fibronectin and fibrinogen interacting with the low affinity form of GPIIb/IIIa and (ii) by antibodies specific to FnBPs that engage the platelet Fc receptor FcgammaRIIa. Platelet activation by S. aureus clinical IE isolates from both the exponential and stationary phases of growth was completely inhibited by monoclonal antibody IV-3 suggesting that the IgG-FcgammaRIIa interaction is of fundamental importance for platelet activation mediated by this organism. This suggests new avenues for development of therapeutics against vascular infections.
authors.affiliation: Department of Microbiology, Moyne Institute of Preventive Medicine, University of Dublin, Trinity College, Dublin, Ireland.
authors.forename: J Ross
authors.initials: JR
authors.lastname: Fitzgerald
authors.forename: Anthony
authors.initials: A
authors.lastname: Loughman
authors.forename: Fiona
authors.initials: F
authors.lastname: Keane
authors.forename: Marian
authors.initials: M
authors.lastname: Brennan
authors.forename: Morris
authors.initials: M
authors.lastname: Knobel
authors.forename: Judy
authors.initials: J
authors.lastname: Higgins
authors.forename: Livia
authors.initials: L
authors.lastname: Visai
authors.forename: Pietro
authors.initials: P
authors.lastname: Speziale
authors.forename: Dermot
authors.initials: D
authors.lastname: Cox
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Foster
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D013294:Lactococcus lactis / Q000378:metabolism; D015539:Platelet Activation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism*
chemical_list: D018829:Adhesins, Bacterial; D015703:Antigens, CD; D001426:Bacterial Proteins; C080568:Fc gamma receptor IIA; D005353:Fibronectins; D007074:Immunoglobulin G; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017452:Receptors, IgG; C078635:fibronectin-binding proteins, bacterial; D005337:Fibrin; D005340:Fibrinogen