Microbes Bind Complement Inhibitor Factor H <i>via</i> a Common Site

<div><p>To cause infections microbes need to evade host defense systems, one of these being the evolutionarily old and important arm of innate immunity, the alternative pathway of complement. It can attack all kinds of targets and is tightly controlled in plasma and on host cells by plasma complement regulator factor H (FH). FH binds simultaneously to host cell surface structures such as heparin or glycosaminoglycans <i>via</i> domain 20 and to the main complement opsonin C3b <i>via</i> domain 19. Many pathogenic microbes protect themselves from complement by recruiting host FH. We analyzed how and why different microbes bind FH via domains 19–20 (FH19-20). We used a selection of FH19-20 point mutants to reveal the binding sites of several microbial proteins and whole microbes (<i>Haemophilus influenzae, Bordetella pertussis</i>, <i>Pseudomonas aeruginosa</i>, <i>Streptococcus pneumonia</i>, <i>Candida albicans</i>, <i>Borrelia burgdorferi</i>, and <i>Borrelia hermsii</i>). We show that all studied microbes use the same binding region located on one side of domain 20. Binding of FH to the microbial proteins was inhibited with heparin showing that the common microbial binding site overlaps with the heparin site needed for efficient binding of FH to host cells. Surprisingly, the microbial proteins enhanced binding of FH19-20 to C3b and down-regulation of complement activation. We show that this is caused by formation of a tripartite complex between the microbial protein, FH, and C3b. In this study we reveal that seven microbes representing different phyla utilize a common binding site on the domain 20 of FH for complement evasion. Binding <i>via</i> this site not only mimics the glycosaminoglycans of the host cells, but also enhances function of FH on the microbial surfaces <i>via</i> the novel mechanism of tripartite complex formation. This is a unique example of convergent evolution resulting in enhanced immune evasion of important pathogens <i>via</i> utilization of a “superevasion site.”</p>