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

Abstract

Significance Antibodies are crucial for the immune response against bacteria. To drive bacterial killing, antibodies should bind to the bacterial cell and induce the complement reaction. This requires target-bound IgGs to form hexameric IgG platforms that are kept together by noncovalent Fc-Fc interactions. Interestingly, pathogenic bacteria produce IgG-binding molecules that bind specifically to the Fc region needed for hexamerization. Here we demonstrate that staphylococcal protein A (SpA) from Staphylococcus aureus specifically blocks formation of IgG hexamers and downstream activation of complement. Furthermore, we show that IgG3 antibodies (which are not recognized by SpA) have superior capacity to activate complement and induce killing of S. aureus by human phagocytes. These insights provide a crucial rationale for optimizing antibody therapies against S. aureus .