TY - JOUR
T1 - Complement factor H allotype 402H is associated with increased C3b opsonization and phagocytosis of Streptococcus pyogenes
AU - Haapasalo, Karita
AU - Jarva, Hanna
AU - Siljander, Tuula
AU - Tewodros, Wezenet
AU - Vuopio-Varkila, Jaana
AU - Jokiranta, T. Sakari
N1 - This article has an erratum:Doi 10.1111/j.1365-2958.2012.07991.x
Volume:
Proceeding volume:
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - HEMOLYTIC-UREMIC SYNDROME
KW - HEPARIN-BINDING DOMAIN
KW - SHORT CONSENSUS REPEAT
KW - GROUP-A STREPTOCOCCI
KW - C-REACTIVE PROTEIN
KW - RCA GENE-CLUSTER
KW - MACULAR DEGENERATION
KW - ALTERNATIVE PATHWAY
KW - C3B/C4B RECEPTOR
KW - SURFACE PROTEIN
KW - 3111 Biomedicine
U2 - 10.1111/j.1365-2958.2008.06347.x
DO - 10.1111/j.1365-2958.2008.06347.x
M3 - Article
VL - 70
SP - 583
EP - 594
JO - Molecular Microbiology
JF - Molecular Microbiology
SN - 0950-382X
IS - 3
ER -