title: Acquisition of complement factor H is important for pathogenesis of Streptococcus pyogenes infections: evidence from bacterial in vitro survival and human genetic association.
abstract: Streptococcus pyogenes (or group A streptococcus [GAS]) is a major human pathogen causing infections, such as tonsillitis, erysipelas, and sepsis. Several GAS strains bind host complement regulator factor H (CFH) via its domain 7 and, thereby, evade complement attack and C3b-mediated opsonophagocytosis. Importance of CFH binding for survival of GAS has been poorly studied because removal of CFH from plasma or blood causes vigorous complement activation, and specific inhibitors of the interaction have not been available. In this study, we found that activation of human complement by different GAS strains (n = 38) correlated negatively with binding of CFH via its domains 5-7. The importance of acquisition of host CFH for survival of GAS in vitro was studied next by blocking the binding with recombinant CFH5-7 lacking the regulatory domains 1-4. Using this fragment in full human blood resulted in death or radically reduced multiplication of all of the studied CFH-binding GAS strains. To study the importance of CFH binding in vivo (i.e., for pathogenesis of streptococcal infections), we used our recent finding that GAS binding to CFH is diminished in vitro by polymorphism 402H, which is also associated with age-related macular degeneration. We showed that allele 402H is suggested to be associated with protection from erysipelas (n = 278) and streptococcal tonsillitis (n = 209) compared with controls (n = 455) (p < 0.05). Taken together, the bacterial in vitro survival data and human genetic association revealed that binding of CFH is important for pathogenesis of GAS infections and suggested that inhibition of CFH binding can be a novel therapeutic approach in GAS infections.
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland. karita.haapasalo@helsinki.fi
authors.forename: Karita
authors.initials: K
authors.lastname: Haapasalo
authors.forename: Jaana
authors.initials: J
authors.lastname: Vuopio
authors.forename: Jaana
authors.initials: J
authors.lastname: Syrjänen
authors.forename: Jari
authors.initials: J
authors.lastname: Suvilehto
authors.forename: Satu
authors.initials: S
authors.lastname: Massinen
authors.forename: Matti
authors.initials: M
authors.lastname: Karppelin
authors.forename: Irma
authors.initials: I
authors.lastname: Järvelä
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: T Sakari
authors.initials: TS
authors.lastname: Jokiranta
mesh_terms: D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology; D004886:Erysipelas / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D055106:Genome-Wide Association Study; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D017434:Protein Structure, Tertiary; D013290:Streptococcal Infections / Q000235:genetics / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology* / Q000472:pathogenicity*; D014069:Tonsillitis / Q000235:genetics / Q000276:immunology / Q000382:microbiology
chemical_list: C493495:CFH protein, human; D017242:Complement Factor H