RT Journal Article
SR Electronic
T1 Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.20.212118
DO 10.1101/2020.07.20.212118
A1 Ana Rita Cruz
A1 Maurits A. den Boer
A1 Jürgen Strasser
A1 Frank J. Beurskens
A1 Carla J. C. de Haas
A1 Piet C. Aerts
A1 Guanbo Wang
A1 Rob N. de Jong
A1 Fabio Bagnoli
A1 Jos A. G. van Strijp
A1 Kok P. M. van Kessel
A1 Janine Schuurman
A1 Johannes Preiner
A1 Albert J. R. Heck
A1 Suzan H. M. Rooijakkers
YR 2020
UL http://biorxiv.org/content/early/2020/07/21/2020.07.20.212118.abstract
AB IgG molecules are essential players in the human immune response against bacterial infections. An important effector of IgG-dependent immunity is the induction of complement activation, a reaction that triggers a variety of responses that help to kill bacteria. Antibody-dependent complement activation is promoted by the organization of target-bound IgGs into hexamers that are held together via noncovalent Fc-Fc interactions. Here we show that Staphylococcal protein A (SpA), an important virulence factor and vaccine candidate of Staphylococcus aureus, effectively blocks IgG hexamerization and subsequent complement activation. Using native mass spectrometry and high-speed atomic force microscopy, we demonstrate that SpA blocks IgG hexamerization through competitive binding to the Fc-Fc interaction interface on IgG monomers. In concordance, we show that SpA interferes with the formation of (IgG)6:C1q complexes and prevents downstream complement activation on the surface of S. aureus. Lastly, we demonstrate that IgG3 antibodies against S. aureus can potently induce complement activation even in the presence of SpA. Altogether, this study identifies SpA as an immune evasion protein that specifically blocks IgG hexamerization.