title: Phagocytosis escape by a Staphylococcus aureus protein that connects complement and coagulation proteins at the bacterial surface.
abstract: Upon contact with human plasma, bacteria are rapidly recognized by the complement system that labels their surface for uptake and clearance by phagocytic cells. Staphylococcus aureus secretes the 16 kD Extracellular fibrinogen binding protein (Efb) that binds two different plasma proteins using separate domains: the Efb N-terminus binds to fibrinogen, while the C-terminus binds complement C3. In this study, we show that Efb blocks phagocytosis of S. aureus by human neutrophils. In vitro, we demonstrate that Efb blocks phagocytosis in plasma and in human whole blood. Using a mouse peritonitis model we show that Efb effectively blocks phagocytosis in vivo, either as a purified protein or when produced endogenously by S. aureus. Mutational analysis revealed that Efb requires both its fibrinogen and complement binding residues for phagocytic escape. Using confocal and transmission electron microscopy we show that Efb attracts fibrinogen to the surface of complement-labeled S. aureus generating a 'capsule'-like shield. This thick layer of fibrinogen shields both surface-bound C3b and antibodies from recognition by phagocytic receptors. This information is critical for future vaccination attempts, since opsonizing antibodies may not function in the presence of Efb. Altogether we discover that Efb from S. aureus uniquely escapes phagocytosis by forming a bridge between a complement and coagulation protein.
authors.affiliation: Center for Infectious and Inflammatory Disease, Institute of Bioscience and Technology, Texas A&M University Health Science Center, Houston, Texas, United States of America.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Ko
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Kuipers
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands ; Utrecht University, Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht, The Netherlands.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Freitag
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands ; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Ilse
authors.initials: I
authors.lastname: Jongerius
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Medina
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Willemien J
authors.initials: WJ
authors.lastname: van Rooijen
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: András N
authors.initials: AN
authors.lastname: Spaan
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kok P M
authors.initials: KP
authors.lastname: van Kessel
authors.affiliation: Center for Infectious and Inflammatory Disease, Institute of Bioscience and Technology, Texas A&M University Health Science Center, Houston, Texas, United States of America.
authors.forename: Magnus
authors.initials: M
authors.lastname: Höök
authors.affiliation: Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Suzan H M
authors.initials: SH
authors.lastname: Rooijakkers
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D001779:Blood Coagulation Factors / Q000378:metabolism; D002478:Cells, Cultured; D003179:Complement C3b / Q000378:metabolism*; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000276:immunology*; D011485:Protein Binding; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology* / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D001779:Blood Coagulation Factors; C114014:Efb protein, Staphylococcus aureus; D003179:Complement C3b; D005340:Fibrinogen