The Staphylococcal Superantigen-Like Protein 7 Binds IgA and Complement C5 and Inhibits IgA-FcαRI Binding and Serum Killing of Bacteria

Abstract

The staphylococcal superantigen-like proteins (SSLs) are close relatives of the superantigens but are coded for by a separate gene cluster within a 19-kb region of the pathogenicity island SaPIn2. rSSL7 (formally known as SET1) bound with high affinity (KD, 1.1 nM) to the monomeric form of human IgA1 and IgA2 plus serum IgA from primate, pig, rat, and horse. SSL7 also bound the secretory form of IgA found in milk from human, cow, and sheep, and inhibited IgA binding to cell surface FcαRI (CD89) and to a soluble form of the FcαRI protein. In addition to IgA, SSL7 bound complement factor C5 from human (KD, 18 nM), primate, sheep, pig, and rabbit serum, and inhibited complement-mediated hemolysis and serum killing of a Gram-negative organism Escherichia coli. SSL7 is a superantigen-like protein secreted from Staphylococcus aureus that blocks IgA-FcR interactions and inhibits complement, leading to increased survival of a sensitive bacterium in blood.

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

“…Interestingly, the SSL7 ␤-grasp domains extend beyond the end of the Fc and are around the expected position of the tail pieces and J-chain that are responsible for the formation of polymeric IgA. We have demonstrated previously that SSL7 binds with high affinity to IgA found in mucosal secretions (22). The relatively flat topography of the current complex may allow the Fc of dimeric IgA to interact concurrently with both secretory component and SSL7.…”

“…Because SSL7 binds serum IgA a role in inhibiting Fc␣RI-mediated effector functions in S. aureus systemic infections is feasible (29,42,43). However, the topography of the SSL7 interaction with Fc may reflect adaptation for its known binding of secretory IgA (22), thereby facilitating mucosal colonization by S. aureus. The existence of functionally equivalent, although unrelated, proteins from group A and group B streptococci (29,30), themselves often mucosal pathogens, suggests the mucosal response is the primary target of these IgA-binding proteins.…”

“…Circulating and secreted IgA differ in form and function (41), and SSL7 binds both with high affinity (22). Because SSL7 binds serum IgA a role in inhibiting Fc␣RI-mediated effector functions in S. aureus systemic infections is feasible (29,42,43).…”

“…This prototypical member of the SSL family of exotoxins (12) can bind with high affinity by comprehensively shielding both sides of the lower half of the Fc, apparently without blocking the additional components (tailpieces, J-chain, and secretory component) that assemble to form dimeric and secretory IgA (22). The Fc residues recognized by SSL7 occur in all human IgA subclasses and allotypes.…”

“…Both SSL5 (21) and SSL11 (M. C. Chung, B.D.W., H. Baker, R. J. Langley, E. N. Baker, and J.D.F., unpublished data) interact with sialyl-Le x and related oligosaccharides, thereby inhibiting key cellular adhesion processes such as neutrophil transmigration. Notably, SSL7 exhibits multiple activities, including the binding of complement component C5 and serum and mucosal forms of IgA, thereby inhibiting both C5 and fragment crystalline (Fc) receptor for IgA (Fc␣RI)-mediated immunity (22,23). Furthermore, SSL7 has been observed to alter cytokine secretion (12) and to bind, and be rapidly internalized by, monocytes and dendritic cells, but the ligands involved are yet to be identified (16,19).…”