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Dual Binding Specificity of a Borrelia hermsii-Associated Complement Regulator-Acquiring Surface Protein for Factor H and Plasminogen Discloses a Putative Virulence Factor of Relapsing Fever Spirochetes^1,2

Evelyn Rossmann^3,*, Peter Kraiczy^3,, Pia Herzberger, Christine Skerka, Michael Kirschfink^*, Markus M. Simon, Peter F. Zipfel and Reinhard Wallich^4,*

^* Infectious Immunology Group, Institute for Immunology, University of Heidelberg, Heidelberg, Germany; Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt, Frankfurt, Germany; Molecular Immunobiology Group and Department of Infection Biology, Leibniz-Institute for Natural Products Research, Jena, Germany; and Metschnikoff Laboratory, Max-Planck-Institute for Immunobiology, Freiburg, Germany

Tick-borne relapsing fever in North America is primarily caused by the spirochete Borrelia hermsii. The pathogen employs multiple strategies, including the acquisition of complement regulators and antigenic variation, to escape innate and humoral immunity. In this study we identified in B. hermsii a novel member of the complement regulator-acquiring surface protein (CRASP) family, designated BhCRASP-1, that binds the complement regulators factor H (FH) and FH-related protein 1 (FHR-1) but not FH-like protein 1 (FHL-1). BhCRASP-1 specifically interacts with the short consensus repeat 20 of FH, thereby maintaining FH-associated cofactor activity for factor I-mediated C3b inactivation. Furthermore, ectopic expression of BhCRASP- 1 converted the serum-sensitive Borrelia burgdorferi B313 strain into an intermediate complement-resistant strain. Finally, we report for the first time that BhCRASP-1 binds plasminogen/plasmin in addition to FH via, however, distinct nonoverlapping domains. The fact that surface-bound plasmin retains its proteolytic activity suggest that the dual binding specificity of BhCRASP-1 for FH and plasminogen/plasmin contributes to both the dissemination/invasion of B. hermsii and its resistance to innate immunity.

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 We are indebted for the financial support of the Deutsche Forschungsgemeinschaft Grants Wa 533/7-1 (to R.W.) and Kr 3383/1-1 (to P.K.). This work forms part of the Ph.D. thesis of E.R. and P.H.

² The sequence presented in this article has been submitted to EMBL/GenBank under accession number AM408562.

³ E.R. and P.K. contributed equally to this work.

⁴ Address correspondence and reprint requests to Dr. Reinhard Wallich, Infectious Immunology Group, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, Heidelberg, Germany. E-mail address: wallich{at}uni-hd.de

⁵ Abbreviations used in this paper: FH, factor H; FHL-1, FH-like protein 1; FHR, FH-related protein; CRASP-1, complement regulator-acquiring surface protein 1; BbCRASP-1, Borrelia burgdorferi CRASP-1; BhCRASP-1, Borrelia hermsii CRASP-1; NHS, normal human serum; Osp, outer surface protein; SCR, short consensus repeat; uPA, urokinase-type plasminogen activator.

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