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

Abstract

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.

Borrelia burgdorferi complement regulator-acquiring surface proteins (BbCRASPs): Expression patterns during the mammal–tick infection cycle

“…produces several different outer surface proteins collectively termed CRASPs (complement regulator-acquiring surface proteins). These lipoproteins share affinities for the host fluid phase negative regulators of complement factor H and/or FHL-1 (factor H-like protein 1) (Hellwage et al, 2001;Kraiczy et al, 2001Kraiczy et al, , 2003Kraiczy et al, , 2004aKraiczy et al, , 2004bAlitalo et al, 2002Alitalo et al, , 2005Stevenson et al, 2002;McDowell et al, 2003;Hartmann et al, 2006;Kraiczy and Würzner, 2006;Herzberger et al, 2007). Those two host proteins promote breakdown of C3b and inactivation of the alternative pathway C3 convertase (Janeway et al, 1999;Kraiczy and Würzner, 2006).…”

Quantitative analysis of Borrelia burgdorferi gene expression in naturally (tick) infected mouse strains

“…For this purpose we have selected one cp26-encoded gene, ospC [40], and four previously described lp54-encoded genes, i.e. ospA, zs7.a36, zs7.a66, and zs7.a68 [20,61]-the respective antigens of which are suggested to be either putative vaccine candidates [61,66] and/or relevant for complement resistence [32]-and three strains of mice with distinct immune status and susceptibility to B. burgdorferi s.s.-induced disease/ infection [50,53].…”

Biology of Infection with Borrelia burgdorferi

“…Considerable attention has been paid to several B. burgdorferi proteins that co-opt the complement regulators factor H and factor H-like proteins, which normally protect mammalian cells from attack by their own complement by blocking activation of the alternative pathway [136][137][138][139][140][141]. Surface coating with factor H could protect the bacteria from killing or opsonization by host complement, facilitating infection.…”