title: Complement factor H allotype 402H is associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes.
abstract: The main virulence factor of group A streptococcus (GAS), M protein, binds plasma complement regulators factor H (FH) and FH-like protein 1 (FHL-1) leading to decreased opsonization. The M protein binding site on FH is within domain 7 in which also the age-related macular degeneration (AMD)-associated polymorphism Y402H is located. We studied if FH allotypes 402H and 402Y have different binding affinities to GAS. Plasma-derived FH allotype 402H and its recombinant fragment FH5-7(402H) showed decreased binding to several GAS strains. Growth of GAS in human blood taken from FH(402H) homozygous individuals was decreased when compared with blood taken from FH(402Y) homozygous individuals. The effect of the allotype 402H can be explained by combining the previous M protein mutagenesis data and the recently published crystal structure of FH6-8. In conclusion the data indicate that the AMD-associated allotype 402H leads to diminished binding of FH to GAS and increased opsonophagocytosis of the bacteria in blood. These results suggest that the homozygous presence of the allele 402H could be associated with decreased risk for severe GAS infections offering an explanation for the high frequency of the allele despite its association with visual impairment.
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Karita
authors.initials: K
authors.lastname: Haapasalo
authors.forename: Hanna
authors.initials: H
authors.lastname: Jarva
authors.forename: Tuula
authors.initials: T
authors.lastname: Siljander
authors.forename: Wezenet
authors.initials: W
authors.lastname: Tewodros
authors.forename: Jaana
authors.initials: J
authors.lastname: Vuopio-Varkila
authors.forename: T Sakari
authors.initials: TS
authors.lastname: Jokiranta
mesh_terms: D000483:Alleles; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology; D003179:Complement C3b / Q000276:immunology / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010587:Phagocytosis / Q000276:immunology*; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013290:Streptococcal Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013297:Streptococcus pyogenes / Q000276:immunology / Q000378:metabolism*; D037521:Virulence Factors / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; C493495:CFH protein, human; D002352:Carrier Proteins; D011994:Recombinant Proteins; D037521:Virulence Factors; C014689:streptococcal M protein; D003179:Complement C3b; D017242:Complement Factor H