title: Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis.
abstract: Neisseria meningitidis (meningococcus) is an important cause of meningitis and sepsis. Currently, there is no effective vaccine against serogroup B meningococcal infection. Host defense against neisseriae requires the complement system (C) as indicated by the fact that individuals deficient in properdin or late C components (C6-9) have an increased susceptibility to recurrent neisserial infections. Because the classical pathway (CP) is required to initiate efficient complement activation on neisseriae, meningococci should be able to evade it to cause disease. To test this hypothesis, we studied the interactions of meningococci with the major CP inhibitor C4b-binding protein (C4bp). We tested C4bp binding to wild-type group B meningococcus strain (H44/76) and to 11 isogenic mutants thereof that differed in capsule expression, lipo-oligosaccharide sialylation, and/or expression of either porin (Por) A or PorB3. All strains expressing PorA bound radiolabeled C4bp, whereas the strains lacking PorA bound significantly less C4bp. Increased binding was observed under hypotonic conditions. Deleting PorB3 did not influence C4bp binding, but the presence of polysialic acid capsule reduced C4bp binding by 50%. Bound C4bp remained functionally active in that it promoted the inactivation of C4b by factor I. PorA-expressing strains were also more resistant to C lysis than PorA-negative strains in a serum bactericidal assay. Binding of C4bp thus helps Neisseria meningitidis to escape CP complement activation.
authors.affiliation: Haartman Institute, Department of Bacteriology and Immunology, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Jarva
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
authors.forename: Ulrich
authors.initials: U
authors.lastname: Vogel
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D001770:Blood Bactericidal Activity / Q000276:immunology; D015935:Complement C4b / Q000378:metabolism*; D050716:Complement C4b-Binding Protein; D003169:Complement Inactivator Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry; D006649:Histocompatibility Antigens / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D038541:Neisseria meningitidis, Serogroup B / Q000378:metabolism*; D018272:Porins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000276:immunology; D012965:Sodium Chloride / Q000737:chemistry; D013045:Species Specificity
chemical_list: C055609:C4BPA protein, human; D050716:Complement C4b-Binding Protein; D003169:Complement Inactivator Proteins; D006649:Histocompatibility Antigens; D018272:Porins; C057699:porin protein, Neisseria; D012965:Sodium Chloride; D015935:Complement C4b; D006493:Heparin