Structural identification of a key protective B-cell epitope in Lyme disease antigen OspA.
Outer surface protein A (OspA) is a major lipoprotein of the Borrelia burgdorferi spirochete, the causative agent of Lyme disease. Vaccination with OspA generates an immune response that can prevent bacterial transmission to a mammalian host during the attachment of an infected tick. However, the protective capacity of immune sera cannot be predicted by measuring total anti-OspA antibody. The murine monoclonal antibody LA-2 defines an important protective B-cell epitope of OspA against which protective sera have strong levels of reactivity. We have now mapped the LA-2 epitope of OspA using both NMR chemical-shift perturbation measurements in solution and X-ray crystal structure determination. LA-2 recognizes the three surface-exposed loops of the C-terminal domain of OspA that are on the tip of the elongated molecule most distant from the lipid-modified N terminus. The structure suggests that the natural variation at OspA sequence position 208 in the first loop is a major limiting factor for antibody cross-reactivity between different Lyme disease-causing Borrelia strains. The unusual Fab-dominated lattice of the crystal also permits a rare view of antigen flexibility within an antigen:antibody complex. These results provide a rationale for improvements in OspA-based vaccines and suggest possible designs for more direct tests of antibody protective levels in vaccinated individuals.
Ding
W
W
Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
Huang
X
X
Yang
X
X
Dunn
J J
JJ
Luft
B J
BJ
Koide
S
S
Lawson
C L
CL
D000595:Amino Acid Sequence; D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000276:immunology; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000954:Antigens, Surface / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D001428:Bacterial Vaccines; D015748:Borrelia burgdorferi Group / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D014644:Genetic Variation / Q000235:genetics; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D008074:Lipoproteins; D008193:Lyme Disease / Q000276:immunology*; D022123:Lyme Disease Vaccines / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D000936:Antigen-Antibody Complex; D000942:Antigens, Bacterial; D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D018985:Epitopes, B-Lymphocyte; D007140:Immunoglobulin Fab Fragments; D008074:Lipoproteins; D022123:Lyme Disease Vaccines; C072045:OspA protein