RT Journal Article
SR Electronic
T1 Staphylococcal protein A inhibits IgG-mediated phagocytosis by blocking the interaction of IgGs with FcγRs and FcRn
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.21.477287
DO 10.1101/2022.01.21.477287
A1 Ana Rita Cruz
A1 Arthur E. H. Bentlage
A1 Robin Blonk
A1 Carla J. C. de Haas
A1 Piet C. Aerts
A1 Lisette M. Scheepmaker
A1 Inge G. Bouwmeester
A1 Anja Lux
A1 Jos A. G. van Strijp
A1 Falk Nimmerjahn
A1 Kok P. M. van Kessel
A1 Gestur Vidarsson
A1 Suzan H. M. Rooijakkers
YR 2022
UL http://biorxiv.org/content/early/2022/01/22/2022.01.21.477287.abstract
AB 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 StatementARC participated in a postgraduate studentship program at GSK. KPMK and SHMR are co-inventor on a patent describing antibody therapies against Staphylococcus aureus.