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Dengue virus antibody database: Systematically linking serotype-specificity with epitope mapping in dengue virus.

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.

journal_name

PLoS Negl Trop Dis

journal_title

PLoS neglected tropical diseases

authors

Chaudhury S,Gromowski GD,Ripoll DR,Khavrutskii IV,Desai V,Wallqvist A

doi

10.1371/journal.pntd.0005395

subject

Has Abstract

pub_date

2017-02-21 00:00:00

pages

e0005395

issue

eissn

1935-2727

issn

1935-2735

pii

PNTD-D-16-01724

journal_volume

pub_type

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Dengue virus antibody database: Systematically linking serotype-specificity with epitope mapping in dengue virus.