Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation

Area of Science:

• Immunology
• Microbiology
• Structural Biology

Background:

• Immunoglobulin G (IgG) is crucial for combating bacterial infections.
• IgG-mediated immunity relies on complement activation, triggered by IgG hexamer formation.
• Staphylococcal protein A (SpA) is a virulence factor of Staphylococcus aureus.

Purpose of the Study:

• To investigate the mechanism by which SpA interferes with IgG function.
• To determine if SpA blocks IgG hexamerization and subsequent complement activation.
• To assess the efficacy of IgG3 antibodies against S. aureus in the presence of SpA.

Main Methods:

• Native mass spectrometry
• High-speed atomic force microscopy
• Analysis of (IgG)6:C1q complex formation
• Assessment of complement activation on S. aureus

Main Results:

• SpA inhibits IgG hexamerization by binding to the Fc-Fc interaction interface.
• SpA prevents the formation of (IgG)6:C1q complexes, blocking complement activation.
• IgG3 antibodies effectively induce complement activation and opsonophagocytic killing despite SpA presence.

Conclusions:

• SpA is identified as an immune evasion protein that specifically targets IgG hexamerization.
• SpA's mechanism involves competitive binding, disrupting a critical step in antibody-dependent immunity.
• IgG3 antibodies represent a potential therapeutic strategy against S. aureus infections, overcoming SpA-mediated immune evasion.