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. 2016 Nov 8:6:36288.
doi: 10.1038/srep36288.

Identification of a New Broadly Cross-reactive Epitope within Domain III of the Duck Tembusu Virus E Protein

Chenxi Li  1 , Xiaofei Bai  1 , Runze Meng  1 , Wulin Shaozhou  1 , Qingshan Zhang  1 , Ronghong Hua  1 , Jyung-Hurng Liu  2 , Ming Liu  1 , Yun Zhang  1
Affiliations

Identification of a New Broadly Cross-reactive Epitope within Domain III of the Duck Tembusu Virus E Protein

Chenxi Li et al. Sci Rep. .

Abstract

In 2010, a pathogenic flavivirus termed duck Tembusu virus (DTMUV) caused widespread outbreak of egg-drop syndrome in domesticated ducks in China. Although the glycoprotein E of DTMUV is an important structural component of the virus, the B-cell epitopes of this protein remains uncharacterized. Using phage display and mutagenesis, we identified a minimal B-cell epitope, 374EXE/DPPFG380, that mediates binding to a nonneutralizing monoclonal antibody. DTMUV-positive duck serum reacted with the epitope, and amino acid substitutions revealed the specific amino acids that are essential for antibody binding. Dot-blot assays of various flavivirus-positive sera indicated that EXE/DPPFG is a cross-reactive epitope in most flaviviruses, including Zika, West Nile, Yellow fever, dengue, and Japanese encephalitis viruses. These findings indicate that the epitope sequence is conserved among many strains of mosquito-borne flavivirus. Protein structure modeling revealed that the epitope is located in domain III of the DTMUV E protein. Together, these results provide new insights on the broad cross-reactivity of a B-cell binding site of the E protein of flaviviruses, which can be exploited as a diagnostic or therapeutic target for identifying, studying, or treating DTMUV and other flavivirus infections.

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Figures

Figure 1
Figure 1. Identification of the E protein epitope.
Peptide fragments were probed for reactivity with the 3B6 mAb by dot-blot assay. YIRTPACWD and full-length DTMUV E protein were used as negative and positive controls, respectively.
Figure 2
Figure 2. Sequence alignment of a minimal epitope in the E protein of flavivirus strains.
The EXE/DPPFG epitope of various strains of DTMUV and other mosquito-borne flaviviruses were aligned using Lasergene software. Amino acid positions for each sequence are numbered on both sides. Dashes indicate identical amino acids. The identified epitope region is indicated by grey shading.
Figure 3
Figure 3. Identification of the E protein minimal epitope by DTMUV-positive duck serum.
Peptide fragments were probed for reactivity with DTMUV-positive duck serum by dot-blot assay. YIRTPACWD and full-length E protein were used as negative and positive controls, respectively.
Figure 4
Figure 4. Cross-reactivity of the E protein minimal epitope with flavivirus-positive sera.
The EVEPPFG epitope was probed for reactivity with various flavivirus-positive sera, including Zika virus (ZIKV), dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and yellow fever virus (YFV), by dot-blot assay. YIRTPACWD (N) and full-length E protein (E) were used as negative and positive controls, respectively.
Figure 5
Figure 5. The EVEPPFG epitope of the DTMUV E protein is located in domain III.
The protein-dimer structure of the DTMUV E protein was modeled using the crystal structure of the JEV E protein as a template. The domain I (DI), domain II (DII), and domain III (DIII) in one E protein monomer are coloured magenta, yellow, and blue, respectively. The other monomer is coloured grey. The location of the epitope is depicted as spheres and labeled. Two predicted N-glycosylation sites are coloured sky blue.
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