title: Streptococcal inhibitor of complement-mediated lysis (SIC): an anti-inflammatory virulence determinant.
abstract: Since the late 1980s, a worldwide increase of severe Streptococcus pyogenes infections has been associated with strains of the M1 serotype, strains which all secrete the streptococcal inhibitor of complement-mediated lysis (SIC). Previous work has shown that SIC blocks complement-mediated haemolysis, inhibits the activity of antibacterial peptides and has affinity for the human plasma proteins clusterin and histidine-rich glycoprotein; the latter is a member of the cystatin protein family. The present work demonstrates that SIC binds to cystatin C, high-molecular-mass kininogen (HK) and low-molecular-mass kininogen, which are additional members of this protein family. The binding sites in HK are located in the cystatin-like domain D3 and the endothelial cell-binding domain D5. Immobilization of HK to cellular structures plays a central role in activation of the human contact system. SIC was found to inhibit the binding of HK to endothelial cells, and to reduce contact activation as measured by prolonged blood clotting time and impaired release of bradykinin. These results suggest that SIC modifies host defence systems, which may contribute to the virulence of S. pyogenes strains of the M1 serotype.
authors: Department of Clinical Sciences, Division of Infection Medicine, Lund University, BMC, B14, SE-22184 Lund, Sweden.
authors: Per
authors: P
authors: Åkesson
authors: Department of Clinical Sciences, Division of Infection Medicine, Lund University, BMC, B14, SE-22184 Lund, Sweden.
authors: Heiko
authors: H
authors: Herwald
authors: Department of Clinical Sciences, Division of Infection Medicine, Lund University, BMC, B14, SE-22184 Lund, Sweden.
authors: Magnus
authors: M
authors: Rasmussen
authors: Department of Laboratory Medicine, Division of Clinical Chemistry and Pharmacology, Lund University, University Hospital, SE-22185 Lund, Sweden.
authors: Katarina
authors: K
authors: HÅkansson
authors: Department of Laboratory Medicine, Division of Clinical Chemistry and Pharmacology, Lund University, University Hospital, SE-22185 Lund, Sweden.
authors: Magnus
authors: M
authors: Abrahamson
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors: Ahmed A K
authors: AAK
authors: Hasan
authors: Department of Medicine, Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH, USA.
authors: Alvin H
authors: AH
authors: Schmaier
authors: Institute for Biochemistry II, University of Frankfurt, Frankfurt, Germany.
authors: Werner
authors: W
authors: Müller-Esterl
authors: Department of Clinical Sciences, Division of Infection Medicine, Lund University, BMC, B14, SE-22184 Lund, Sweden.
authors: Lars
authors: L
authors: Björck
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D003165:Complement System Proteins; D055316:Cystatin C / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000276:immunology; D011485:Protein Binding; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D055316:Cystatin C; D019679:Kininogen, High-Molecular-Weight; C097739:SIC protein, Streptococcus; D003165:Complement System Proteins