title: Streptococcus pneumoniae evades complement attack and opsonophagocytosis by expressing the pspC locus-encoded Hic protein that binds to short consensus repeats 8-11 of factor H.
abstract: Streptococcus pneumoniae is an important cause of upper and lower respiratory tract infections, meningitis, peritonitis, bacterial arthritis, and sepsis. Here we have studied a novel immune evasion mechanism of serotype 3 pneumococci, which are particularly resistant to phagocytosis. On their surfaces the bacteria express the factor H-binding inhibitor of complement (Hic), a protein of the pneumococcal surface protein C family. Using radioligand binding, microtiter plate assays, surface plasmon resonance analysis, and recombinant constructs of factor H, we located the binding site of Hic to short consensus repeats (SCRs) 8-11 in the middle part of factor H. This represents a novel microbial interaction region on factor H. The only other ligand known so far for SCRs 8-11 of factor H is C-reactive protein (CRP), an acute phase protein that binds to the pneumococcal C-polysaccharide. The binding sites of Hic and CRP within the SCR8-11 region were different, however, because CRP did not inhibit the binding of Hic and required calcium for binding. Binding of factor H to Hic-expressing pneumococci promoted factor I-mediated cleavage of C3b and restricted phagocytosis of pneumococci. Thus, virulent pneumococci avoid complement attack and opsonophagocytosis by recruiting functionally active factor H with the Hic surface protein. Hic binds to a previously unrecognized microbial interaction site in the middle part of factor H.
authors.affiliation: Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. hanna.jarva@helsinki.fi
authors.forename: Hanna
authors.initials: H
authors.lastname: Jarva
authors.forename: Robert
authors.initials: R
authors.lastname: Janulczyk
authors.forename: Jens
authors.initials: J
authors.lastname: Hellwage
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Lars
authors.initials: L
authors.lastname: Björck
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
mesh_terms: D001426:Bacterial Proteins; D001665:Binding Sites; D001667:Binding, Competitive; D002097:C-Reactive Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003167:Complement Activation; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016384:Consensus Sequence; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007700:Kinetics; D009895:Opsonin Proteins / Q000276:immunology; D010587:Phagocytosis; D011994:Recombinant Proteins / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D017384:Sequence Deletion; D013296:Streptococcus pneumoniae / Q000378:metabolism / Q000472:pathogenicity*; D020349:Surface Plasmon Resonance
chemical_list: D001426:Bacterial Proteins; C493495:CFH protein, human; D002352:Carrier Proteins; C417512:Hic protein, Streptococcus pneumoniae; D009895:Opsonin Proteins; D011994:Recombinant Proteins; D003179:Complement C3b; D017242:Complement Factor H; D002097:C-Reactive Protein