title: Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway.
abstract: Human fibrinogen (Fg) binds to surface proteins expressed by many pathogenic bacteria and has been implicated in different host-pathogen interactions, but the role of bound Fg remains unclear. Here, we analyse the role of Fg bound to Streptococcus pyogenes M protein, a major virulence factor that confers resistance to phagocytosis. Studies of the M5 system showed that a chromosomal mutant lacking the Fg-binding region was completely unable to resist phagocytosis, indicating that bound Fg plays a key role in virulence. Deposition of complement on S. pyogenes occurred via the classical pathway even under non-immune conditions, but was blocked by M5-bound Fg, which reduced the amount of classical pathway C3 convertase on the bacterial surface. This property of M protein-bound Fg may explain its role in phagocytosis resistance. Previous studies have shown that many M proteins do not bind Fg, but interfere with complement deposition and phagocytosis by recruiting human C4b-binding protein (C4BP), an inhibitor of the classical pathway. Thus, all M proteins may share ability to recruit a human plasma protein, Fg or C4BP, which inhibits complement deposition via the classical pathway. Our data identify a novel function for surface-bound Fg and allow us to propose a unifying mechanism by which M proteins interfere with innate immunity.
authors.affiliation: Department of Medical Microbiology, Dermatology and Infection, Lund University, Sölvegatan 23, SE-22362 Lund, Sweden.
authors.forename: Fredric
authors.initials: F
authors.lastname: Carlsson
authors.forename: Charlotta
authors.initials: C
authors.lastname: Sandin
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindahl
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000187:drug effects* / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding; D013297:Streptococcus pyogenes / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; C014689:streptococcal M protein; D005340:Fibrinogen; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases