AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses
- 6 February 2017
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 114 (8), 2024-2029
- https://doi.org/10.1073/pnas.1620558114
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
This publication has 52 references indexed in Scilit:
- TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated PhosphatidylserinePLoS Pathogens, 2013
- Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasisThe Journal of Experimental Medicine, 2012
- The TIM and TAM Families of Phosphatidylserine Receptors Mediate Dengue Virus EntryCell Host & Microbe, 2012
- Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoproteinVirology, 2011
- The Soluble Serum Protein Gas6 Bridges Virion Envelope Phosphatidylserine to the TAM Receptor Tyrosine Kinase Axl to Mediate Viral EntryCell Host & Microbe, 2011
- Structural basis for the preferential recognition of immature flaviviruses by a fusion-loop antibodyThe EMBO Journal, 2009
- Maturation of West Nile Virus Modulates Sensitivity to Antibody-Mediated NeutralizationPLoS Pathogens, 2008
- Structure of the Immature Dengue Virus at Low pH Primes Proteolytic MaturationScience, 2008
- Structure of Immature West Nile VirusJournal of Virology, 2007
- DC-SIGN (CD209) Mediates Dengue Virus Infection of Human Dendritic CellsThe Journal of Experimental Medicine, 2003