Streptococcal inhibitor of complement (SIC) modulates fibrinolysis and enhances bacterial survival within fibrin clots

J Biol Chem. 2018 Aug 31;293(35):13578-13591. doi: 10.1074/jbc.RA118.001988. Epub 2018 Jul 12.

Abstract

Some strains of the bacterial pathogen Streptococcus pyogenes secrete protein SIC (streptococcal inhibitor of complement), including strains of the clinically relevant M1 serotype. SIC neutralizes the effect of a number of antimicrobial proteins/peptides and interferes with the function of the host complement system. Previous studies have shown that some S. pyogenes proteins bind and modulate coagulation and fibrinolysis factors, raising the possibility that SIC also may interfere with the activity of these factors. Here we show that SIC interacts with both human thrombin and plasminogen, key components of coagulation and fibrinolysis. We found that during clot formation, SIC binds fibrin through its central region and that SIC inhibits fibrinolysis by interacting with plasminogen. Flow cytometry results indicated that SIC and plasminogen bind simultaneously to S. pyogenes bacteria, and fluorescence microscopy revealed co-localization of the two proteins at the bacterial surface. As a consequence, SIC-expressing bacteria entrapped in clots inhibit fibrinolysis, leading to delayed bacterial escape from the clots as compared with mutant bacteria lacking SIC. Moreover, within the clots SIC-expressing bacteria were protected against killing. In an animal model of subcutaneous infection, SIC-expressing bacteria exhibited a delayed systemic spread. These results demonstrate that the bacterial protein SIC interferes with coagulation and fibrinolysis and thereby enhances bacterial survival, a finding that has significant implications for S. pyogenes virulence.

Keywords: Streptococcus pyogenes (S. pyogenes); antimicrobial agent; bacterial clearance; fibrinolysis; group A streptococci; innate immunity; plasminogen; streptococcal inhibitor of complement; thrombin; virulence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / immunology*
  • Complement System Proteins / immunology
  • Female
  • Fibrin / immunology
  • Fibrinogen / immunology
  • Fibrinolysis*
  • Humans
  • Immunity, Innate
  • Mice
  • Mice, Inbred C57BL
  • Streptococcal Infections / complications
  • Streptococcal Infections / immunology*
  • Streptococcal Infections / microbiology
  • Streptococcus pyogenes / immunology*
  • Thrombin / immunology
  • Thrombosis / complications
  • Thrombosis / immunology*
  • Thrombosis / microbiology

Substances

  • Bacterial Proteins
  • SIC protein, Streptococcus
  • Fibrin
  • Fibrinogen
  • Complement System Proteins
  • Thrombin