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

Ana Rita Cruz, Maurits A. den Boer, Jürgen Strasser, Seline A. Zwarthoff, Frank J. Beurskens, Carla J.C. de Haas, Piet C. Aerts, Guanbo Wang, Rob N. de Jong, Fabio Bagnoli, Jos A.G. van Strijp, Kok P.M. van Kessel, Janine Schuurman, Johannes Preiner, Albert J.R. Heck, Suzan H.M. Rooijakkers

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Immunoglobulin (Ig) G 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 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. Finally, we demonstrate that IgG3 antibodies against S. aureus can potently induce complement activation and opsonophagocytic killing even in the presence of SpA. Together, our findings identify SpA as an immune evasion protein that specifically blocks IgG hexamerization.

Original languageEnglish
Article numbere2016772118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number7
DOIs
Publication statusPublished - 16 Feb 2021

Keywords

  • Antibodies | complement | IgG hexamerization | staphylococcal protein A | Staphylococcus aureus
  • Immunoglobulin G/metabolism
  • Complement Activation
  • Humans
  • Protein Multimerization
  • Cells, Cultured
  • Staphylococcus aureus/immunology
  • Staphylococcal Protein A/metabolism
  • Immunoglobulin Fc Fragments/metabolism
  • Protein Binding
  • Phagocytes/immunology
  • Binding Sites
  • Phagocytosis

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