S. aureus IgG-binding proteins SpA and Sbi: host specificity and mechanisms of immune complex formation.
The evasion of the host immune response is central to the pathogenicity of Staphylococcus aureus, and is facilitated by the ability of the cell wall-associated protein A (SpA) to bind immunoglobulin G Fc fragments, thereby impeding phacocytosis and classical pathway complement fixation. SpA also acts as a B-cell superantigen through interactions with the heavy-chain variable part of Fab fragments, and sequesters immunoglobulins by forming large insoluble immune complexes with human IgG. Here we show that the formation of insoluble immune complexes is mediated by the binding of (VH3+) Fab fragments in addition to Fc, and that SpA forms soluble complexes with IgG Fc fragments. We compared these results with those for Sbi, a second staphylococcal immunoglobulin-binding protein, and note that this protein requires only the Fc fragment for precipitation with human IgG. Homology models of immunoglobulin-binding domains of SpA and Sbi in complex with Fc reveal the molecular basis of the Fab-independent formation of insoluble complexes by Sbi. Finally, we compared the sequences of the spa and sbi genes from human strains to those infecting a range of animal hosts to determine whether Sbi and SpA have acquired specificity for host IgG. We note remarkable sequence conservation within the IgG-binding domains of these genes, consistent with a lack of host specificity. The Fab-independent binding of IgG by Sbi could have significant clinical implications. The use of SpA in immunoadsorption therapy can cause severe side-effects, thought to be mediated by Fc gamma R recognition and complement fixation. The formation of insoluble immune complexes with Sbi occurs only via Fc binding and free Fc regions are unlikely to be available for Fc gamma R recognition and complement fixation.
Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
Karen L
KL
Atkins
Julia D
JD
Burman
Emily S
ES
Chamberlain
Jessica E
JE
Cooper
Bernard
B
Poutrel
Stefan
S
Bagby
A Toby A
AT
Jenkins
Edward J
EJ
Feil
Jean M H
JM
van den Elsen
D000595:Amino Acid Sequence; D000818:Animals; D000936:Antigen-Antibody Complex / Q000737:chemistry* / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000276:immunology; D002352:Carrier Proteins / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000276:immunology*
D000936:Antigen-Antibody Complex; D001426:Bacterial Proteins; D002352:Carrier Proteins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; C112405:Sbi protein, Staphylococcus aureus