Streptococcal inhibitor of complement-mediated lysis (SIC): an anti-inflammatory virulence determinant

Area of Science:

• Microbiology
• Immunology
• Biochemistry

Background:

• Severe Streptococcus pyogenes infections, particularly M1 serotype strains, have increased globally since the late 1980s.
• These M1 strains secrete streptococcal inhibitor of complement-mediated lysis (SIC), which is known to interfere with host immune responses.
• Previous studies indicated SIC interacts with human plasma proteins like clusterin and histidine-rich glycoprotein, a cystatin family member.

Purpose of the Study:

• To investigate the interaction of SIC with additional members of the cystatin protein family.
• To determine the functional consequences of SIC binding to high-molecular-mass kininogen (HK) and its role in the human contact system.
• To elucidate how SIC contributes to the virulence of M1 Streptococcus pyogenes.

Main Methods:

• Protein-protein interaction assays to demonstrate SIC binding to cystatin C, HK, and low-molecular-mass kininogen.
• Identification of SIC binding sites within the HK protein.
• In vitro assays measuring the inhibition of HK binding to endothelial cells.
• Assessment of contact system activation via blood clotting time and bradykinin release.

Main Results:

• SIC was confirmed to bind to cystatin C, high-molecular-mass kininogen (HK), and low-molecular-mass kininogen.
• Specific binding sites for SIC on HK were identified in domains D3 and D5.
• SIC significantly inhibited the binding of HK to endothelial cells.
• SIC reduced contact system activation, evidenced by prolonged blood clotting times and impaired bradykinin release.

Conclusions:

• SIC interacts with multiple cystatin family proteins, including HK.
• SIC's inhibition of HK-endothelial cell binding and contact system activation suggests a mechanism for evading host defenses.
• These findings highlight SIC's role in the virulence of M1 Streptococcus pyogenes, contributing to severe infections.