title: Interaction with C4b-binding protein contributes to nontypeable Haemophilus influenzae serum resistance.
abstract: Complement evasion by various mechanisms is important for microbial virulence and survival in the host. One strategy used by some pathogenic bacteria is to bind the complement inhibitor of the classical pathway, C4b-binding protein (C4BP). In this study, we have identified a novel interaction between nontypeable Haemophilus influenzae (NTHi) and C4BP, whereas the majority of the typeable H. influenzae (a-f) tested showed no binding. One of the clinical isolates, NTHi 506, displayed a particularly high binding of C4BP and was used for detailed analysis of the interaction. Importantly, a low C4BP-binding isolate (NTHi 69) showed an increased deposition of C3b followed by reduced survival as compared with NTHi 506 when exposed to normal human serum. The main isoform of C4BP contains seven identical alpha-chains and one beta-chain linked together with disulfide bridges. Each alpha-chain is composed of eight complement control protein (CCP) modules and we have found that the NTHi 506 strain did not interact with rC4BP lacking CCP2 or CCP7 showing that these two CCPs are important for the binding. Importantly, C4BP bound to the surface of H. influenzae retained its cofactor activity as determined by analysis of C3b and C4b degradation. Taken together, NTHi interferes with the classical complement activation pathway by binding to C4BP.
authors.affiliation: Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
authors.forename: Teresia
authors.initials: T
authors.lastname: Hallström
authors.forename: Hanna
authors.initials: H
authors.lastname: Jarva
authors.forename: Kristian
authors.initials: K
authors.lastname: Riesbeck
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D001665:Binding Sites / Q000276:immunology; D003179:Complement C3b / Q000037:antagonists & inhibitors / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D050716:Complement C4b-Binding Protein / Q000378:metabolism* / Q000502:physiology; D003171:Complement Pathway, Classical / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D006192:Haemophilus Infections / Q000276:immunology / Q000382:microbiology; D006193:Haemophilus influenzae / Q000145:classification / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D011485:Protein Binding / Q000276:immunology; D015610:Serum Bactericidal Test; D013045:Species Specificity
chemical_list: D050716:Complement C4b-Binding Protein; D003179:Complement C3b; D015935:Complement C4b