Staphylococcal protein A inhibits complement activation by interfering with IgG hexamer formation
Cruz, Ana Rita; den Boer, Maurits A.; Strasser, Jürgen; Zwarthoff, Seline A.; Beurskens, Frank J.; de Haas, Carla J.C.; Aerts, Piet C.; Wang, Guanbo; de Jong, Rob N.; Bagnoli, Fabio; van Strijp, Jos A.G.; van Kessel, Kok P.M.; Schuurman, Janine; Preiner, Johannes; Heck, Albert J.R.; Rooijakkers, Suzan H.M.
(2021) Proceedings of the National Academy of Sciences of the United States of America, volume 118, issue 7, pp. 1 - 11
(Article)
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
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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.
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Keywords: Antibodies | complement | IgG hexamerization | staphylococcal protein A | Staphylococcus aureus, IgG hexamerization, antibodies, complement, Staphylococcus aureus, staphylococcal protein A, 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, General, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: ACKNOWLEDGMENTS. We thank Annette Stemerding for fruitful discussions. This research is supported by the Dutch Technology Foundation STW, which is part of the Netherlands Organisation for Scientific Research (NWO), and which is partly funded by Ministry of Economic Affairs (TTW-NACTAR Grant #16442 [to AJRH and SHMR]). This work was supported by the European Union’s Horizon 2020 research program H2020-MSCA-ITN (675106, to J.A.G.v.S. and F.B.), and a European Research Council (ERC) Starting Grant (639209, to S.H.M.R.). M.A.d.B. and A.J.R.H. further acknowledge funding for the large-scale proteomics facility, the Netherlands Proteomics Center, through the X-omics Road Map program (Project 184.034.019) and the EU Horizon 2020 program Epic-XS (Project 823839). A.J.R.H. and S.H.M.R. acknowledge the Utrecht University Molecular Immunology Hub. J.P. receives support from the European Fund for Regional Development (EFRE, IWB2020), the Federal State of Upper Austria, and the Austrian Science Fund (FWF, P33958 and P34164). Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved. Copyright © 2021 the Author(s). Published by PNAS.
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