title: Streptococcus pneumoniae phosphoglycerate kinase is a novel complement inhibitor affecting the membrane attack complex formation.
abstract: The Gram-positive bacterium Streptococcus pneumoniae is a major human pathogen that causes infections ranging from acute otitis media to life-threatening invasive disease. Pneumococci have evolved several strategies to circumvent the host immune response, in particular the complement attack. The pneumococcal glycolytic enzyme phosphoglycerate kinase (PGK) is both secreted and bound to the bacterial surface and simultaneously binds plasminogen and its tissue plasminogen activator tPA. In the present study we demonstrate that PGK has an additional role in modulating the complement attack. PGK interacted with the membrane attack complex (MAC) components C5, C7, and C9, thereby blocking the assembly and membrane insertion of MAC resulting in significant inhibition of the hemolytic activity of human serum. Recombinant PGK interacted in a dose-dependent manner with these terminal pathway proteins, and the interactions were ionic in nature. In addition, PGK inhibited C9 polymerization both in the fluid phase and on the surface of sheep erythrocytes. Interestingly, PGK bound several MAC proteins simultaneously. Although C5 and C7 had partially overlapping binding sites on PGK, C9 did not compete with either one for PGK binding. Moreover, PGK significantly inhibited MAC deposition via both the classical and alternative pathway at the pneumococcal surface. Additionally, upon activation plasmin(ogen) bound to PGK cleaved the central complement protein C3b thereby further modifying the complement attack. In conclusion, our data demonstrate for the first time to our knowledge a novel pneumococcal inhibitor of the terminal complement cascade aiding complement evasion by this important pathogen.
authors.affiliation: From the Section of Medical Protein Chemistry, Department of Laboratory Medicine Malmö, Lund University, 20502 Malmö, Sweden, anna.blom@med.lu.se.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.affiliation: Institute of Microbiology, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625 Hannover, Germany, and.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fulde
authors.affiliation: Section of Medical Microbiology, Department of Laboratory Medicine Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Kristian
authors.initials: K
authors.lastname: Riesbeck
authors.affiliation: From the Section of Medical Protein Chemistry, Department of Laboratory Medicine Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Agarwal
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003167:Complement Activation / Q000187:drug effects; D003179:Complement C3b / Q000378:metabolism; D003182:Complement C5 / Q000378:metabolism; D003184:Complement C7 / Q000378:metabolism; D003186:Complement C9 / Q000378:metabolism; D051056:Complement Inactivating Agents / Q000378:metabolism* / Q000494:pharmacology; D015938:Complement Membrane Attack Complex / Q000187:drug effects / Q000378:metabolism*; D003165:Complement System Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism; D005434:Flow Cytometry; D006461:Hemolysis; D006801:Humans; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D058105:Polymerization / Q000187:drug effects; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D044967:Serum / Q000378:metabolism; D012756:Sheep; D013296:Streptococcus pneumoniae / Q000201:enzymology* / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D003182:Complement C5; D003184:Complement C7; D003186:Complement C9; D051056:Complement Inactivating Agents; D015938:Complement Membrane Attack Complex; D011994:Recombinant Proteins; D003179:Complement C3b; D010958:Plasminogen; D003165:Complement System Proteins; D010735:Phosphoglycerate Kinase
keywords: Bacterial Pathogenesis; Complement; Complement Inhibitor; Host-Pathogen Interaction; Membrane Attack Complex; Plasminogen; Pneumococci; Streptococcus