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Interaction of Zika Virus Envelope Protein with Glycosaminoglycans
journal contribution
posted on 2017-02-02, 00:00 authored by So Young Kim, Jing Zhao, Xinyue Liu, Keith Fraser, Lei Lin, Xing Zhang, Fuming Zhang, Jonathan S. Dordick, Robert J. LinhardtIn
February 2016, the World Health Organization declared a Public
Health Emergency of International Concern on Zika Virus (ZIKV), because
of its association with severe fetal anomalies of congenitally infected
humans. This has led to urgent efforts by academic, federal, and industry
research groups to improve our understanding of the pathogenesis of
ZIKV and to develop detection methods, therapeutic strategies, and
vaccines. Although we still do not have the entire picture of the
pathogenesis of ZIKV, extensive research has been conducted on related
pathogenic flaviviruses (i.e., dengue virus, West Nile virus, and
yellow fever virus). Binding to glycosaminoglycans (GAGs) through
its envelope protein is the first step in successful host cell invasion
of dengue virus. In this study, we examined ZIKV envelope protein
(ZIKV E) binding to GAGs in a real time interaction study using surface
plasmon resonance (SPR) to explore the role of GAGs in host cell entry
of ZIKV into placenta and brain. ZIKV E strongly binds (KD = 443 nM) pharmaceutical heparin (HP), a highly sulfated
GAG, and binds with lower avidity to less sulfated GAGs, suggesting
that the ZIKV E–GAG interaction may be electrostatically driven.
Using SPR competition assays with various chain length HP oligosaccharides
(from 4 to 18 saccharide units in length), we observed that ZIKV E
preferentially binds to longer HP oligosaccharides (with 8–18
saccharides). Next, we examined GAGs prepared from human placentas
to determine if they bound ZIKV E, possibly mediating placental cell
invasion of ZIKV. Compositional analysis of these GAGs as well as
SPR binding studies showed that both chondroitin sulfate and heparan
sulfate GAGs, present on the placenta, showed low-micromolar interactions
with ZIKV E. Both porcine brain CS and HS also showed micromolar binding
with ZIKV E. Moreover, heparan sulfate with a higher TriS content,
the dominant repeating unit of HP, shows a high affinity for ZIKV
E. These results suggest that GAGs may be utilized as attachment factors
for host cell entry of Zika virus as they do in other pathogenic flaviviruses.
They may also assist us in advancing our understanding of the pathogenesis
of ZIKV and guide us in designing therapeutics to combat ZIKV with
more insight.
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chain length HP oligosaccharidesSPR competition assayshost cell entryWorld Health Organizationplacental cell invasionZIKV E18 saccharide unitsindustry research groupsHSSPR binding studieshost cell invasiontime interaction studyPublic Health EmergencyZika Virus Envelope Proteinsurface plasmon resonanceZIKV envelope proteinWest Nile virusheparan sulfate GAGsporcine brain CS
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