A Competitive Mechanism for Staphylococcal Toxin SSL7 Inhibiting the Leukocyte IgA Receptor, FcαRI, Is Revealed by SSL7 Binding at the Cα2/Cα3 Interface of IgA

Bruce D Wines,Natasha Willoughby,John D Fraser,P.Mark Hogarth

doi:10.1074/jbc.m509334200

Bruce D Wines, Natasha Willoughby + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m509334200

Copy DOI

Abstract

Leukocyte recruitment and effector functions like phagocytosis and respiratory burst are key elements of immunity to infection. Pathogen survival is dependent upon the ability to overwhelm, evade or inhibit the immune system. Pathogenic group A and group B streptococci are well known to produce virulence factors that block the binding of IgA to the leukocyte IgA receptor, Fc alphaRI, thereby inhibiting IgA-mediated immunity. Recently we found Staphylococcus aureus also interferes with IgA-mediated effector functions as the putative virulence factor SSL7 also binds IgA and blocks binding to Fc alphaRI. Herein we report that SSL7 and Fc alphaRI bind many of the same key residues in the Fc region of human IgA. Residues Leu-257 and Leu-258 in domain C alpha2 and residues 440-443 PLAF in C alpha3 of IgA lie at the C alpha2/C alpha3 interface and make major contributions to the binding of both the leukocyte receptor Fc alphaRI and SSL7. It is remarkable this S. aureus IgA binding factor and unrelated factors from streptococci are functionally convergent, all targeting a number of the same residues in the IgA Fc, which comprise the binding site for the leukocyte IgA receptor, Fc alphaRI.

Highlights

An unrelated protein, is capable of multiple interactions targeting the host immune response, including binding TNFR1 (12), C1qR (13), and IgG via VH3 Fabs (14) and the Fc at the C␥2/C␥3 interface region (15)
SSL7 Inhibits Fc␣RI-Ig Binding to IgA Fc—The Fc region of human IgA1 derived from Dakiki cells was fused to the N-terminal region of the transferrin receptor, a type II integral membrane protein
S. aureus infection of the bloodstream can lead to septicemia, and asymptomatic carriage of S. aureus can occur in the nose while life-threatening infections of the respiratory tract occur (12)

Summary

Introduction

An unrelated protein, is capable of multiple interactions targeting the host immune response, including binding TNFR1 (12), C1qR (13), and IgG via VH3 Fabs (14) and the Fc at the C␥2/C␥3 interface region (15). This study investigated the site of human IgA binding to SSL7. SSL7 was found to bind to the C␣2/C␣3 interface of IgA Fc and require residues essential for the interaction of Fc␣RI with IgA. The SSL7 and Fc␣RI binding sites are likely to be the same or at least closely overlapping. The interaction of SSL7 was independent of the IgA Asn-263 linked carbohydrate, which extends close to the C␣2/C␣3 interface (16)

Methods

Results

Conclusion