title: Assessment of the interaction of human complement regulatory proteins with group A Streptococcus. Identification of a high-affinity group A Streptococcus binding site in FHL-1.
abstract: Group A Streptococcus (GAS), the most frequent bacterial cause of suppurative infections in humans, expresses on the cell surface M proteins with capacity to bind factor H, FHL-1 and C4b binding protein (C4BP). This has been interpreted as a mechanism developed by this pathogen to decrease phagocytosis by macrophages and polymorphonuclear cells. We report the analysis of the capacity to bind factor H, FHL-1 and C4BP of 69 clinical isolates from 19 different serotypes. We show that strains binding complement regulators (30/69) belong to specific M serotypes. Of these, M18 strains are relatively frequent and interact with all three complement regulators simultaneously. However, the most virulent M1 and M3 strains did not bind complement regulators in our assays. The relevance of the interaction between complement regulators and S. pyogenes was analyzed using different approaches with the conclusion that under physiological conditions only FHL-1 and C4BP bind to streptococci. We show that FHL-1 presents a higher binding affinity for S. pyogenes than factor H because it carries a hydrophobic, high-affinity, GAS binding site in addition to the heparin binding site in SCR7. Using synthetic peptides we provide evidence that the high-affinity GAS binding site in FHL-1 involves the hydrophobic tail (Ser-Phe-Thr-Leu) that distinguishes FHL-1 from factor H.
authors.affiliation: Departamento de Inmunología, CIB (CSIC), Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Pérez-Caballero
authors.forename: S
authors.initials: S
authors.lastname: Albertí
authors.forename: F
authors.initials: F
authors.lastname: Vivanco
authors.forename: P
authors.initials: P
authors.lastname: Sánchez-Corral
authors.forename: S
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D000595:Amino Acid Sequence; D000942:Antigens, Bacterial; D000954:Antigens, Surface / Q000032:analysis / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins / Q000032:analysis / Q000378:metabolism; D001667:Binding, Competitive; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D017242:Complement Factor H / Q000737:chemistry* / Q000378:metabolism*; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011951:Receptors, Complement / Q000097:blood / Q000378:metabolism*; D012703:Serotyping; D013290:Streptococcal Infections / Q000097:blood / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000145:classification* / Q000378:metabolism* / Q000472:pathogenicity; D013816:Thermodynamics
chemical_list: D000942:Antigens, Bacterial; D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; C493495:CFH protein, human; D002352:Carrier Proteins; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D010446:Peptide Fragments; D011951:Receptors, Complement; C014689:streptococcal M protein; D017242:Complement Factor H; D006493:Heparin