Natural Human Immunity Against Staphylococcal Protein A Relies on Effector Functions Triggered by IgG3.

Elena Boero,Suzan H M Rooijakkers,Andrea G O Manetti,Kok P M Van Kessel,Werner Pansegrau,Jos A G Van Strijp,Fabio Bagnoli,Ana Rita Cruz,Cinzia Giovani

doi:10.3389/fimmu.2022.834711

Elena Boero, Suzan H M Rooijakkers + Show 7 more

Open Access

https://doi.org/10.3389/fimmu.2022.834711

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Abstract

Staphylococcal protein A (SpA) is a multifunctional, highly conserved virulence factor of Staphylococcus aureus. By binding the Fc portion of all human IgG subclasses apart from IgG3, SpA interferes with antibody and complement deposition on the bacterial surface, impairing staphylococcal clearance by phagocytosis. Because of its anti-opsonic properties, SpA is not investigated as a surface antigen to mediate bacterial phagocytosis. Herein we investigate human sera for the presence of SpA-opsonizing antibodies. The screening revealed that sera containing IgG3 against SpA were able to correctly opsonize the target and drive Fcγ receptor-mediated interactions and phagocytosis. We demonstrated that IgG3 Fc is significantly more efficient in inducing phagocytosis of SpA-expressing S. aureus as compared to IgG1 Fc in an assay resembling physiological conditions. Furthermore, we show that the capacity of SpA antibodies to induce phagocytosis depends on the specific epitope recognized by the IgGs on SpA molecules. Overall, our results suggest that anti-SpA IgG3 antibodies could favor the anti-staphylococcal response in humans, paving the way towards the identification of a correlate of protection against staphylococcal infections.

Highlights

Staphylococcus aureus is a Gram-positive human commensal and pathogen causing a broad variety of community and healthcare-associated infections [1]
The importance of opsonins in the host defense of S. aureus is emphasized by studies showing that C3 deficiencies [7], neutrophil dysfunctions [8, 9], and the expression of certain Fc gamma receptor (FcgR) alleles [10] render patients more susceptible to staphylococcal infections, suggesting that opsonophagocytosis is a crucial mechanism for staphylococcal clearance [4, 5, 9, 11–13]
Sera and plasma samples from 116 S. aureus-infected subjects or healthy controls were screened for the presence of anti-SpA wild type (SpAwt) opsonizing antibodies (Table 1)

Summary

INTRODUCTION

Staphylococcus aureus is a Gram-positive human commensal and pathogen causing a broad variety of community and healthcare-associated infections [1]. Phagocytosis is more effective when the bacterial surface is tagged with host opsonins such as Abbreviations: C1, Complement protein 1; CDR, Complementarity determining regions; CR, Complement receptor; Fab, Fragment, antigen-binding; Fc, Fragment, crystallizable; FcgR, Fc gamma receptor; IgG, Immunoglobulin G; mAb, Monoclonal antibody; MRSA, Methicillin-resistant S. aureus; OR, Odd ratio; SpA, Staphylococcal Protein A; TNFR, Tumor Necrosis Factor a Receptor; VRSA, Vancomycin-resistant S. aureus; vWF, von Willebrand factor. We show that the position of binding site of specific anti-SpA IgG3 on SpA molecules affects the capacity of these antibodies to opsonize saturated bacteria These data add important information to our knowledge of the anti-SpA immune response and suggest the role of IgG3 and its binding site position as a potentially relevant factor concurring to define a humoral correlate of protection against S. aureus infections, and the possible use of monoclonal antibodies as therapeutics against infectious diseases

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ETHICS STATEMENT