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.
Highlights
Some strains of the bacterial pathogen Streptococcus pyogenes secrete protein SIC, including strains of the clinically relevant M1 serotype
To investigate whether SIC has affinity for thrombin, SIC purified from S. pyogenes strain AP1 or produced in Escherichia coli using recombinant expression was applied to PVDF filters that were incubated with radiolabeled prothrombin or thrombin
In response to bacterial infection and inflammation the coagulation system is activated, and at the site of infection fibrin clot formation leads to bacterial entrapment
Summary
Some strains of the bacterial pathogen Streptococcus pyogenes secrete protein SIC (streptococcal inhibitor of complement), including strains of the clinically relevant M1 serotype. 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. The coagulation system is rapidly activated upon vascular injury, whereby a fibrin clot is generated and blood is loss prevented This system comprises two pathways, the extrinsic (tissue factor pathway) and the intrinsic pathway ( known as the contact system) Whereas tPA cleaves the molecule at a specific site generating the active two-chain plasmin [5], streptokinase causes activation by forming a complex with plasminogen This complex formation leads to the exposure of the active center in plasminogen, whereby the molecule is activated without any cleavage. The demonstration that proteolysis of thrombin [17] and thrombin cleavage of bacteria-bound fibrinogen [18] generates peptides with antibacterial activity further links coagulation to innate immunity
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