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. 2017 Feb 21;11(2):e0005395.
doi: 10.1371/journal.pntd.0005395. eCollection 2017 Feb.

Dengue Virus Antibody Database: Systematically Linking Serotype-Specificity With Epitope Mapping in Dengue Virus

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Free PMC article

Dengue Virus Antibody Database: Systematically Linking Serotype-Specificity With Epitope Mapping in Dengue Virus

Sidhartha Chaudhury et al. PLoS Negl Trop Dis. .
Free PMC article

Abstract

Background: A majority infections caused by dengue virus (DENV) are asymptomatic, but a higher incidence of severe illness, such as dengue hemorrhagic fever, is associated with secondary infections, suggesting that pre-existing immunity plays a central role in dengue pathogenesis. Primary infections are typically associated with a largely serotype-specific antibody response, while secondary infections show a shift to a broadly cross-reactive antibody response.

Methods/principal findings: We hypothesized that the basis for the shift in serotype-specificity between primary and secondary infections can be found in a change in the antibody fine-specificity. To investigate the link between epitope- and serotype-specificity, we assembled the Dengue Virus Antibody Database, an online repository containing over 400 DENV-specific mAbs, each annotated with information on 1) its origin, including the immunogen, host immune history, and selection methods, 2) binding/neutralization data against all four DENV serotypes, and 3) epitope mapping at the domain or residue level to the DENV E protein. We combined epitope mapping and activity information to determine a residue-level index of epitope propensity and cross-reactivity and generated detailed composite epitope maps of primary and secondary antibody responses. We found differing patterns of epitope-specificity between primary and secondary infections, where secondary responses target a distinct subset of epitopes found in the primary response. We found that secondary infections were marked with an enhanced response to cross-reactive epitopes, such as the fusion-loop and E-dimer region, as well as increased cross-reactivity in what are typically more serotype-specific epitope regions, such as the domain I-II interface and domain III.

Conclusions/significance: Our results support the theory that pre-existing cross-reactive memory B cells form the basis for the secondary antibody response, resulting in a broadening of the response in terms of cross-reactivity, and a focusing of the response to a subset of epitopes, including some, such as the fusion-loop region, that are implicated in poor neutralization and antibody-dependent enhancement of infection.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Dengue virus antibody database.
Each monoclonal antibody in the database is annotated with information about its origin and selection, activity against all four dengue serotypes, epitope mapping, and relevant references.
Fig 2
Fig 2. Serotype-specificity and epitope mapping in primary and secondary dengue infections.
A) Histograms of human mAbs in the primary (left) and secondary infection (right) data sets. B) Epitope propensity in primary (left) and secondary (right) infections across E protein amino acid sequence. Points are colored with respect to epitope cross-reactivity, or the proportion of mAbs that are associated with a given epitope residue that are classified as ‘complex’: red (>60%), orange (30–60%), or yellow (< 30%). C) A composite map of epitope propensity and cross-reactivity on the structure of the DENV E protein dimer for mAbs from primary (left) and secondary (right) infections. Epitope regions DI/DII interface, dimer interface, fusion loop, DII/DIII interface, and DIII-lateral ridge (LR) are highlighted. Spheres correspond to epitope residues. The size of the sphere corresponds to its epitope propensity: low propensity (<5%, small spheres), medium propensity (>5% and <10%; medium spheres), and high propensity (>10%, large spheres). The color of the sphere corresponds to the epitope cross-reactivity as described above.
Fig 3
Fig 3. Sequence variation and serotype specificity in DENV mAbs.
A) Histogram of sequence conservation among DENV 1–4 E protein epitope residues for type-specific and complex mAbs from primary and secondary infections, compared with all residues in the E protein. B) Sequence variation between consensus sequences of DENV1-4, at the epitope level measured by the average pepitope for type-specific mAbs from primary infection (N = 45), complex mAbs from primary infection (N = 24), and complex mAbs from secondary infections (N = 25). Only mAbs with epitope definitions consisting of at least five residues were considered. Error bars correspond to the standard deviation of pepitope values. A statistically significant difference is indicated by ‘*’, corresponding to p < 0.001.
Fig 4
Fig 4. Differences in epitope fine-specificity between mouse and human.
Mapping of epitope propensity on to the structure of the DENV E protein dimer for mAbs from mouse (A) and human (B). Spheres correspond to epitope residues. The size of the sphere corresponds to its epitope propensity, as described previously. C. Difference in epitope propensity between mouse and human across the E protein. Residue color corresponds to domain—purple, cyan, and magenta, for DI, DII, and DIII, respectively.

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Grant support

The authors were supported by the U.S. Army Medical Research and Materiel Command (Ft. Detrick, MD) and the Military Infectious Disease Research Program (Grant# Z0010-TC-OC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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