The Staphylococcus aureus Protein Sbi Acts as a Complement Inhibitor and Forms a Tripartite Complex with Host Complement Factor H and C3b

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Abstract
The Gram-positive bacterium Staphylococcus aureus, similar to other pathogens, binds human complement regulators Factor H and Factor H related protein 1 (FHR-1) from human serum. Here we identify the secreted protein Sbi (Staphylococcus aureus binder of IgG) as a ligand that interacts with Factor H by a—to our knowledge—new type of interaction. Factor H binds to Sbi in combination with C3b or C3d, and forms tripartite Sbi∶C3∶Factor H complexes. Apparently, the type of C3 influences the stability of the complex; surface plasmon resonance studies revealed a higher stability of C3d complexed to Sbi, as compared to C3b or C3. As part of this tripartite complex, Factor H is functionally active and displays complement regulatory activity. Sbi, by recruiting Factor H and C3b, acts as a potent complement inhibitor, and inhibits alternative pathway-mediated lyses of rabbit erythrocytes by human serum and sera of other species. Thus, Sbi is a multifunctional bacterial protein, which binds host complement components Factor H and C3 as well as IgG and β2-glycoprotein I and interferes with innate immune recognition. Staphylococcus aureus is a Gram-positive bacterium that can live as a commensal but can also cause severe life threatening infections in humans. Upon infection the bacterium is attacked by the host immune system, and in particular by the complement system which forms the immediate, first defence line of innate immunity. In order to survive, S. aureus has developed multiple evasion strategies and uses several virulence factors to evade and inactivate the host complement attack. Here we show that this pathogen binds the host complement regulators Factor H from human serum with the secreted and surface exposed Sbi protein, by a—to our knowledge—new type of interaction. Factor H binds to Sbi in combination with another host complement protein C3, C3b or C3d, and forms tripartite Sbi∶C3∶Factor H complexes. As part of this tripartite complex, Factor H is functionally active and inhibits further complement activation. Sbi, by recruiting Factor H and C3b, acts as a potent complement inhibitor, and inhibits alternative pathway-mediated lyses of rabbit erythrocytes by human serum and sera of different species. Thus, Sbi is a multifunctional bacterial protein, which binds host complement components Factor H and C3 as well as IgG and β2-glycoprotein I and interferes with innate immune recognition.