Abstract
Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXL-dependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL.
Keywords:
AXL; Flaviviruses; Zika virus; fetal endothelial cell; placental barrier.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axl Receptor Tyrosine Kinase
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Cell Line
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Dengue Virus / physiology
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Human Umbilical Vein Endothelial Cells / metabolism*
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Humans
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Insecta
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Intercellular Signaling Peptides and Proteins / metabolism*
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Microcephaly / virology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA Helicases / isolation & purification
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RNA Interference
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RNA, Small Interfering / metabolism
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Real-Time Polymerase Chain Reaction
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Serine Endopeptidases / isolation & purification
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Viral Nonstructural Proteins / isolation & purification
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Virus Internalization*
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West Nile virus / physiology
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Zika Virus / isolation & purification
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Zika Virus / pathogenicity
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Zika Virus / physiology*
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Zika Virus Infection / pathology*
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Zika Virus Infection / virology
Substances
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Intercellular Signaling Peptides and Proteins
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NS3 protein, flavivirus
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Viral Nonstructural Proteins
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growth arrest-specific protein 6
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Receptor Protein-Tyrosine Kinases
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Serine Endopeptidases
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RNA Helicases
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Axl Receptor Tyrosine Kinase