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

Abstract

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.

Structure of Factor H-binding Protein B (FhbB) of the Periopathogen, Treponema denticola

“…K D values for other FH CCP7/microbially produced FH-binding protein interactions have been reported to be in the nanomolar range (25,26). Although the K D value for the FH/FhbB interaction indicates a weak interaction, it is similar to that reported for the interaction of FH with most host-derived ligands (40,41 (25,26,42). As discussed in detail below, the biological role that FH binding plays in T. denticola pathogenesis may be facilitated by the rapid off kinetics of the FhbB/FH interaction.…”

Complement Factor H-Binding Protein, a Putative Virulence Determinant of Borrelia hermsii, Is an Antigenic Target for Protective B1b Lymphocytes

“…Deletion of the B. burgdorferi gene encoding for CRASP-1 results in a dramatic increase in serum sensitivity, while genetic complementation of CRASP-1 promotes serum resistance (43). Analogous to the complement resistance property exhibited by the related pathogen B. burgdorferi, expression of FhbA may facilitate B. hermsii in achieving serum resistance (6,28,30,44). Because the constitutive expression of FhbA is presumably vital for B. hermsii survival in the host, such molecules provide an attractive antigenic target for the host immune system.…”

Identification of an Antiparallel Coiled-Coil/Loop Domain Required for Ligand Binding by theBorrelia hermsiiFhbA Protein: Additional Evidence for the Role of FhbA in the Host-Pathogen Interaction

“…This protein has also been referred to as BhCRASP-1 (52). However, since BhCRASP-1 displays high amino acid identity with FhbA, we continue to employ the original FhbA nomenclature (27).…”