title: Antibodies against a secreted product of Staphylococcus aureus trigger phagocytic killing.
abstract: Host immunity against bacteria typically involves antibodies that recognize the microbial surface and promote phagocytic killing. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of lethal bloodstream infection; however, vaccines and antibody therapeutics targeting staphylococcal surface molecules have thus far failed to achieve clinical efficacy. S. aureus secretes coagulase (Coa), which activates host prothrombin and generates fibrin fibrils that protect the pathogen against phagocytosis by immune cells. Because of negative selection, the coding sequence for the prothrombin-binding D1-D2 domain is highly variable and does not elicit cross-protective immune responses. The R domain, tandem repeats of a 27-residue peptide that bind fibrinogen, is conserved at the C terminus of all Coa molecules, but its functional significance is not known. We show here that the R domain enables bloodstream infections by directing fibrinogen to the staphylococcal surface, generating a protective fibrin shield that inhibits phagocytosis. The fibrin shield can be marked with R-specific antibodies, which trigger phagocytic killing of staphylococci and protect mice against lethal bloodstream infections caused by a broad spectrum of MRSA isolates. These findings emphasize the critical role of coagulase in staphylococcal escape from opsonophagocytic killing and as a protective antigen for S. aureus vaccines.
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637.
authors.forename: Lena
authors.initials: L
authors.lastname: Thomer
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637.
authors.forename: Carla
authors.initials: C
authors.lastname: Emolo
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637.
authors.forename: Vilasack
authors.initials: V
authors.lastname: Thammavongsa
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637.
authors.forename: Hwan Keun
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637.
authors.forename: Molly E
authors.initials: ME
authors.lastname: McAdow
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kieffer
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637 oschnee@bsd.uchicago.edu dmissiak@bsd.uchicago.edu.
authors.forename: Olaf
authors.initials: O
authors.lastname: Schneewind
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637 oschnee@bsd.uchicago.edu dmissiak@bsd.uchicago.edu.
authors.forename: Dominique
authors.initials: D
authors.lastname: Missiakas
mesh_terms: D000371:Agglutination; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D003030:Coagulase / Q000737:chemistry / Q000276:immunology*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D009895:Opsonin Proteins / Q000378:metabolism; D010587:Phagocytosis; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D013203:Staphylococcal Infections / Q000097:blood / Q000276:immunology / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D003030:Coagulase; D009895:Opsonin Proteins; D005337:Fibrin