Toward Understanding How Staphylococcal Protein A Inhibits IgG-Mediated Phagocytosis

Ana Rita Cruz, Arthur E H Bentlage, Robin Blonk, Carla J C de Haas, Piet C Aerts, Lisette M Scheepmaker, Inge G Bouwmeester, Anja Lux, Jos A G van Strijp, Falk Nimmerjahn, Kok P M van Kessel, Gestur Vidarsson, Suzan H M Rooijakkers

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

IgG molecules are crucial for the human immune response against bacterial infections. IgGs can trigger phagocytosis by innate immune cells, like neutrophils. To do so, IgGs should bind to the bacterial surface via their variable Fab regions and interact with Fcγ receptors and complement C1 via the constant Fc domain. C1 binding to IgG-labeled bacteria activates the complement cascade, which results in bacterial decoration with C3-derived molecules that are recognized by complement receptors on neutrophils. Next to FcγRs and complement receptors on the membrane, neutrophils also express the intracellular neonatal Fc receptor (FcRn). We previously reported that staphylococcal protein A (SpA), a key immune-evasion protein of Staphylococcus aureus, potently blocks IgG-mediated complement activation and killing of S. aureus by interfering with IgG hexamer formation. SpA is also known to block IgG-mediated phagocytosis in absence of complement, but the mechanism behind it remains unclear. In this study, we demonstrate that SpA blocks IgG-mediated phagocytosis and killing of S. aureus and that it inhibits the interaction of IgGs with FcγRs (FcγRIIa and FcγRIIIb, but not FcγRI) and FcRn. Furthermore, our data show that multiple SpA domains are needed to effectively block IgG1-mediated phagocytosis. This provides a rationale for the fact that SpA from S. aureus contains four to five repeats. Taken together, our study elucidates the molecular mechanism by which SpA blocks IgG-mediated phagocytosis and supports the idea that in addition to FcγRs, the intracellular FcRn is also prevented from binding IgG by SpA.

Original languageEnglish
Pages (from-to)1146-1155
Number of pages10
JournalJournal of Immunology
Volume209
Issue number6
DOIs
Publication statusPublished - 15 Sept 2022

Keywords

  • Complement C1
  • Humans
  • Immunoglobulin G/immunology
  • Phagocytosis
  • Receptors, Complement
  • Receptors, IgG/metabolism
  • Staphylococcal Protein A/metabolism
  • Staphylococcus aureus

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