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Staphylococcal protein A inhibits IgG-mediated phagocytosis by blocking the interaction of IgGs with FcγRs and FcRn

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, View ORCID ProfileGestur Vidarsson, View ORCID ProfileSuzan H. M. Rooijakkers
doi: https://doi.org/10.1101/2022.01.21.477287
Ana Rita Cruz
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
2GSK, Siena, Italy
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Arthur E. H. Bentlage
3Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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Robin Blonk
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Carla J. C. de Haas
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Piet C. Aerts
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Lisette M. Scheepmaker
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Inge G. Bouwmeester
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Anja Lux
4Division of Genetics, Department of Biology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91058, Germany
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Jos A. G. van Strijp
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Falk Nimmerjahn
4Division of Genetics, Department of Biology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91058, Germany
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Kok P. M. van Kessel
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Gestur Vidarsson
3Department of Experimental Immunohematology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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  • ORCID record for Gestur Vidarsson
Suzan H. M. Rooijakkers
1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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  • ORCID record for Suzan H. M. Rooijakkers
  • For correspondence: s.h.m.rooijakkers@umcutrecht.nl
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Abstract

Immunoglobulin G 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 (FcγRs) 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 (CRs) on neutrophils. Next to FcγRs and CRs 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. Here we demonstrate that SpA blocks IgG-mediated phagocytosis and killing of S. aureus through inhibition of 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 next to FcγRs, also the intracellular FcRn receptor is essential for efficient phagocytosis and killing of bacteria by neutrophils.

Competing Interest Statement

ARC participated in a postgraduate studentship program at GSK. KPMK and SHMR are co-inventor on a patent describing antibody therapies against Staphylococcus aureus.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 22, 2022.
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Staphylococcal protein A inhibits IgG-mediated phagocytosis by blocking the interaction of IgGs with FcγRs and FcRn
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
bioRxiv 2022.01.21.477287; doi: https://doi.org/10.1101/2022.01.21.477287
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Staphylococcal protein A inhibits IgG-mediated phagocytosis by blocking the interaction of IgGs with FcγRs and FcRn
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
bioRxiv 2022.01.21.477287; doi: https://doi.org/10.1101/2022.01.21.477287

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