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J. Biol. Chem., Vol. 279, Issue 4, 2421-2429, January 23, 2004

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Complement Resistance of Borrelia burgdorferi Correlates with the Expression of BbCRASP-1, a Novel Linear Plasmid-encoded Surface Protein That Interacts with Human Factor H and FHL-1 and Is Unrelated to Erp Proteins^*

Peter Kraiczy, Jens Hellwage¶, Christine Skerka¶, Heiko Becker||, Michael Kirschfink||, Markus M. Simon**, Volker Brade, Peter F. Zipfel¶, and Reinhard Wallich||

From the Institute of Medical Microbiology, University Hospital of Frankfurt, Paul-Ehrlich-Strasse 40, D-60596 Frankfurt, the ^¶Molecular Immunobiology Group and Department of Infection Biology, Hans-Knoell-Institute for Natural Products Research, Beutenbergstrasse 11a, D-07745 Jena, the ^||Department of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, and the ^**Max-Planck-Institute for Immunobiology, Stübeweg 51, D-79108 Freiburg, Germany

The etiologic agent of Lyme disease, Borrelia burgdorferi, is capable of circumventing the immune defense of a variety of potential vertebrate hosts. Previous work has shown that interaction of host-derived complement regulators, factor H and factor H-like protein 1 (FHL-1), with up to five complement regulator-acquiring surface proteins (CRASPs) expressed by resistant B. burgdorferi sensu lato isolates conferred complement resistance. In addition expression of CRASP-1 is directly correlated with complement resistance of Borrelia species. This work describes the functional characterization of BbCRASP-1 as the dominant factor H and FHL-1-binding protein of B. burgdorferi. The corresponding gene, zs7.a68, is located on the linear plasmid lp54 and is different from factor H-binding Erp proteins that are encoded by genes localized on circular plasmids (cp32). Deletion mutants of BbCRASP-1 were generated, and a high affinity binding site for factor H and FHL-1 was mapped to the C terminus of BbCRASP-1. Similarly, the predominant binding site of factor H and FHL-1 was localized to the short consensus repeat 7. Factor H and FHL-1 maintain their cofactor activity for factor I-mediated C3b inactivation when bound to BbCRASP-1, and factor H is up to 6-fold more efficient in mediating C3b conversion than FHL-1. In conclusion, BbCRASP-1 (i) binds the host complement regulators factor H and FHL-1 with high affinity, (ii) is the key molecule of the complement resistance of spirochetes, and (iii) is distinct from the Erp protein family. Thus, BbCRASP-1 most likely contributes to persistence of B. burgdorferi and to pathogenesis of Lyme disease.

Received for publication, July 30, 2003 , and in revised form, November 6, 2003.

^* This work was supported by the Thüringer Ministerium für Wissenschaft, Forschung und Kultur and the Deutsche Forschungsgemeinschaft Projects Zi 432/5 and Br 446/11-4. 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ430845.

To whom correspondence and reprints requests should be addressed: Institute of Medical Microbiology, University Hospital of Frankfurt, Paul-Ehrlich-Str. 40, D-60596 Frankfurt, Germany. Tel.: 49-69-6301-7165; Fax: 49-69-6301-5767; E-mail: Kraiczy{at}em.unifrankfurt.de.

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