Haapasalo Karita, Jarva Hanna, Siljander Tuula, Tewodros Wezenet, Vuopio-Varkila Jaana, Jokiranta T Sakari
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
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.
A组链球菌（GAS）的主要毒力因子M蛋白与血浆补体调节因子H（FH）和FH样蛋白1（FHL-1）结合，导致调理作用减弱。FH上的M蛋白结合位点位于结构域7内，年龄相关性黄斑变性（AMD）相关的多态性Y402H也位于该结构域。我们研究了FH异型402H和402Y对GAS的结合亲和力是否不同。血浆来源的FH异型402H及其重组片段FH5-7(402H)与几种GAS菌株的结合减少。与从FH(402Y)纯合个体采集的血液相比，从FH(402H)纯合个体采集的人血中GAS的生长减少。结合先前的M蛋白诱变数据和最近发表的FH6-8晶体结构，可以解释异型402H的作用。总之，数据表明AMD相关的异型402H导致FH与GAS的结合减少，并增加了血液中细菌的调理吞噬作用。这些结果表明，等位基因402H的纯合存在可能与严重GAS感染风险降低有关，这为该等位基因尽管与视力损害有关但仍具有高频率提供了解释。
