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bioRxiv · 10.1101/2024.04.29.591597

Structure of a human monoclonal antibody in complex with Outer surface protein C (OspC) of the Lyme disease spirochete, Borreliella burgdorferi

Rudolph, M.·Chen, Y.·Vorauer, C.·Vance, D.·Piazza, C. L.·Willsey, G. G.·McCarthy, K.·Muriuki, B.·Cavacini, L.·Guttman, M.·Mantis, N. J.
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Abstract

Lyme disease is a tick-borne, multisystem infection caused by the spirochete, Borreliella burgdorferi. Although antibodies have been implicated in the resolution of Lyme disease, the specific B cell epitopes targeted during human infections remain largely unknown. In this study, we characterized and defined the structural epitope of a patient-derived bactericidal monoclonal IgG ("B11") against Outer surface protein C (OspC), a homodimeric lipoprotein necessary for B. burgdorferi tick-mediated transmission and early-stage colonization of vertebrate hosts. High-resolution epitope mapping was accomplished through hydrogen deuterium exchange-mass spectrometry (HDX-MS) and X-ray crystallography. Structural analysis of B11 Fab-OspCA complexes revealed the B11 Fabs associated in a 1:1 stoichiometry with the lateral faces of OspCA homodimers such that the antibodies are essentially positioned perpendicular to the spirochetes outer surface. B11s primary contacts reside within the membrane proximal regions of -helices 1 and 6 and adjacent loops 5 and 6 in one OspCA monomer. In addition, B11 spans the OspCA dimer interface, engaging opposing -helix 1, -helix 2, and loop 2-3 in the second OspCA monomer. The B11-OspCA structure is reminiscent of the recently solved mouse transmission blocking monoclonal IgG B5 in complex with OspCA, indicating a mode of engagement with OspC that is conserved across species. In conclusion, we provide the first detailed insight into the interaction between a functional human antibody and an immunodominant Lyme disease antigen long considered an important vaccine target.

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Rudolph, M., Chen, Y., Vorauer, C., Vance, D., Piazza, C. L., Willsey, G. G., McCarthy, K., Muriuki, B., Cavacini, L., Guttman, M., Mantis, N. J.. 2024-04-30. Structure of a human monoclonal antibody in complex with Outer surface protein C (OspC) of the Lyme disease spirochete, Borreliella burgdorferi. https://doi.org/10.1101/2024.04.29.591597

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