Complement factor H allotype 402H is associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes

Mol Microbiol. 2008 Nov;70(3):583-94. doi: 10.1111/j.1365-2958.2008.06347.x. Epub 2008 Jun 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antigens, Bacterial / immunology
  • Antigens, Bacterial / metabolism
  • Bacterial Outer Membrane Proteins / immunology
  • Bacterial Outer Membrane Proteins / metabolism
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism
  • Complement Activation / immunology
  • Complement C3b / immunology
  • Complement C3b / metabolism*
  • Complement Factor H / genetics
  • Complement Factor H / immunology
  • Complement Factor H / metabolism
  • Homozygote
  • Humans
  • Mutagenesis, Site-Directed
  • Mutation
  • Phagocytosis / immunology*
  • Polymorphism, Genetic
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / metabolism
  • Streptococcal Infections / genetics
  • Streptococcal Infections / immunology
  • Streptococcal Infections / metabolism
  • Streptococcus pyogenes / immunology
  • Streptococcus pyogenes / metabolism*
  • Virulence Factors / immunology
  • Virulence Factors / metabolism


  • Antigens, Bacterial
  • Bacterial Outer Membrane Proteins
  • CFH protein, human
  • Carrier Proteins
  • Recombinant Proteins
  • Virulence Factors
  • streptococcal M protein
  • Complement C3b
  • Complement Factor H