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Cutting Edge: Members of the Staphylococcus aureus Extracellular Fibrinogen-Binding Protein Family Inhibit the Interaction of C3d with Complement Receptor 2¹

Daniel Ricklin^*, Salome K. Ricklin-Lichtsteiner^*, Maciej M. Markiewski^*, Brian V. Geisbrecht and John D. Lambris^2,*

^* Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; and Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri, Kansas City, MO 64110

Staphylococcus aureus expresses a highly diversified arsenal of immune evasion proteins, many of which target the complement system. The extracellular fibrinogen-binding protein (Efb) and the Efb homologous protein (Ehp) have previously been demonstrated to bind to C3 and inhibit complement activation and amplification. In this study we present the first evidence that Efb and Ehp are also capable of inhibiting the interaction of C3d with complement receptor 2 (CR2), which plays an important role in B cell activation and maturation. The C-terminal domain of Efb efficiently blocked this interaction both in surface plasmon resonance-based competition studies and cellular assays and prevented the CR2-mediated stimulation of B cells. Furthermore, analyses of the available structural data were consistent with a molecular mechanism that reflects both steric and electrostatic effects on the C3d-CR2 interaction. Our study therefore suggests that S. aureus may disrupt both the innate and adaptive immune responses with a single protein module.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI30040, AI068730, and AI071028.

² Address correspondence and reprint requests to Dr. John D. Lambris, 401 Stellar-Chance Laboratories, 422 Curie Boulevard, University of Pennsylvania, Philadelphia, PA 19104. E-mail address: lambris{at}upenn.edu

³ Abbreviations used in this paper: Efb, extracellular fibrinogen-binding protein; CR2, complement receptor type 2; Efb-C, C-terminal domain of Efb; Ehp, Efb homologous protein; RU, resonance units; pC3, polymeric glutaraldehyde-aggregated C3; RA/NA, R131A/N138A mutations; SCR, short consensus repeat domain; SPR, surface plasmon resonance.