Toward Understanding How Staphylococcal Protein A Inhibits IgG-Mediated Phagocytosis

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.

A single-cell transcriptomic atlas of the lungs of patients with pulmonary tuberculosis

“…Consistently, IgG levels were elevated in the TB disease tissues (Fig. 2f), suggesting an exacerbated IgG production, which may facilitate IgGmediated phagocytosis and clearance of invading bacteria in TB tissues 77 . Altogether, our analysis reveal that TB infection results in a vigorous immunoinflammatory response, followed by recruitment of numerous immune cells to infected sites.…”

Immunoglobulin G subclasses confer protection against Staphylococcus aureus bloodstream dissemination through distinct mechanisms in mouse models

“…We suspect that 3F6-mIgG3 protection in BALB/cJ mice is the result of augmented C1q recruitment. With respect to 3F6-mIgG1, we suspect that the abundance of SpA and the fact that each SpA molecule can be labeled with five 3F6 molecules on the bacterial surface are sufficient to compensate for weak C1q and FcγRs interactions; further SpA does not interact with mIgG1-Fcγ and thus cannot block the effector functions of this subclass ( 31 , 60 ). However, how can we account for the distinct activities of the same antibody, 3F6-mIgG2a, in two mouse strains?…”

Nuclease activity and protein A release of Staphylococcus aureus clinical isolates determine the virulence in a murine model of acute lung infection

“…On the one hand neutrophils and keratinocytes respond to SpA by secreting pro-inflammatory cytokines such as IL8, TNFα, or MIP1α in vitro , and the release of NETs ( 31 , 32 ). On the other hand SpA is known to protect S. aureus from IgG-mediated phagocytosis, to induce shedding of the TNFR, and was suggested to neutralize TNFα ( 12 – 14 ). Surprisingly, we did not observe differences regarding phagocytosis between USA300 and low 17 or high 81 , most likely due to differences within the experimental setting.…”

“…Another factor receiving more and more attention is staphylococcal protein A (SpA), which belongs to the microbial surface components recognizing adhesive matrix molecules (MSCRMMs) ( 11 ). SpA binds non-specifically to the Fc-regions of IgGs, thereby hindering phagocytosis ( 12 ). Additionally, it suppresses the host immune response by early shedding of the tumor necrosis factor receptor -1 (TNFR-1) from the cell surface in an ADAM17-dependent manner, thus, preventing downstream signaling ( 13 ) and neutralizing soluble TNFα in the inflammatory environment ( 14 ).…”