Immune evasion of Borrelia burgdorferi: mapping of a complement‐inhibitor factor H‐binding site of BbCRASP‐3, a novel member of the Erp protein family

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Abstract
The causative agents of Lyme disease, Borrelia burgdorferi s.s., B. garinii, and B. afzelii, differ in their susceptibility to complement‐mediated lysis. This phenomenon apparently depends on the expression of proteins termed complement regulator‐acquiring surface proteins (CRASP) and their binding to the inhibitory plasma proteins factor H and FHL‐1. To characterize these bacterial proteins in more detail we have now isolated from a B. burgdorferi expression library a novel factor H‐binding protein. In accordance with our previous studies this protein was termed BbCRASP‐3 and represents a novel member of the polymorphic Erp (OspE/F‐related) protein family. On the basis of protease accessibility assays using intact spirochetes, BbCRASP‐3 isidentified as a surface‐exposed protein and binds the C‐terminal short consensus repeats of factor H. Applying deletion mutants of BbCRASP‐3, the factor H‐binding site was mapped to the nine‐amino‐acid motif LEVLKKNLK localized at the C‐terminal end of BbCRASP‐3. Factor H bound to BbCRASP‐3 maintains its cofactor activity in factor I‐mediated C3b inactivation. Binding of BbCRASP‐3 to factor H can be inhibited by heparin, a physiological ligand of the complement regulator factor H. Blocking of factor‐H‐binding by soluble BbCRASP‐3 leads to an increase of complement deposition on intermediate serum‐resistant strain ZS7. In conclusion, BbCRASP‐3 has been identified as a novel factor H‐binding protein on B. burgdorferi which by conferring complement resistance to the pathogen may contribute to its persistence in the mammalian host.