Structure of a Human Monoclonal Antibody in Complex with Outer Surface Protein C of the Lyme Disease Spirochete, Borreliella burgdorferi.

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  • Additional Information
    • Source:
      Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE
    • Publication Information:
      Publication: Bethesda, MD : American Association of Immunologists
      Original Publication: Baltimore : Williams & Wilkins, c1950-
    • Subject Terms:
      Bacterial Outer Membrane Proteins*/immunology ; Bacterial Outer Membrane Proteins*/chemistry ; Lyme Disease*/immunology ; Borrelia burgdorferi*/immunology ; Antibodies, Monoclonal*/immunology ; Antibodies, Monoclonal*/chemistry ; Antigens, Bacterial*/immunology ; Antigens, Bacterial*/chemistry; Humans ; Crystallography, X-Ray ; Antibodies, Bacterial/immunology ; Epitope Mapping/methods ; Immunoglobulin G/immunology ; Epitopes, B-Lymphocyte/immunology ; Epitopes, B-Lymphocyte/chemistry ; Animals ; Immunoglobulin Fab Fragments/immunology ; Immunoglobulin Fab Fragments/chemistry
    • Abstract:
      Lyme disease is a tick-borne, multisystem infection caused by the spirochete Borreliella burgdorferi. Although Abs 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 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 Abs are essentially positioned perpendicular to the spirochete's outer surface. B11's primary contacts reside within the membrane-proximal regions of α-helices 1 and 6 and adjacent loops 5 and 6 in one OspCA monomer. In addition, B11 spans the OspCA dimer interface, engaging opposing α-helix 1', α-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 a detailed insight into the interaction between a functional human Ab and an immunodominant Lyme disease Ag long considered an important vaccine candidate.
      (Copyright © 2024 by The American Association of Immunologists, Inc.)
    • Comments:
      Update of: bioRxiv. 2024 May 03:2024.04.29.591597. doi: 10.1101/2024.04.29.591597. (PMID: 38746285)
    • Grant Information:
      75N93019C00040 United States AI NIAID NIH HHS; 75N93019C00040 United States AI NIAID NIH HHS
    • Accession Number:
      0 (Bacterial Outer Membrane Proteins)
      0 (Antibodies, Monoclonal)
      0 (OspC protein)
      0 (Antigens, Bacterial)
      0 (Antibodies, Bacterial)
      0 (Immunoglobulin G)
      0 (Epitopes, B-Lymphocyte)
      0 (Immunoglobulin Fab Fragments)
    • Publication Date:
      Date Created: 20240906 Date Completed: 20241007 Latest Revision: 20241008
    • Publication Date:
      20241009
    • Accession Number:
      10.4049/jimmunol.2400247
    • Accession Number:
      39240158