AXL-dependent Infection of Human Fetal Endothelial Cells Distinguishes Zika Virus from Other Pathogenic Flaviviruses

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2017 Feb 8

PMID 28167751

Citations 123

Authors

Audrey Stephanie Richard

Byoung-Shik Shim

Young-Chan Kwon

Rong Zhang

Yuka Otsuka

Kimberly Schmitt

Fatma Berri

Michael S Diamond

Hyeryun Choe

Affiliations

Soon will be listed here.

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.

Citing Articles

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The ability of human TIM1 to bind phosphatidylethanolamine enhances viral uptake and efferocytosis compared to rhesus and mouse orthologs.

Zhang L, Kitzmiller C, Richard A, Popli S, Choe H J Virol. 2024; 98(11):e0164924.

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Chronic innate immune impairment and ZIKV persistence in the gastrointestinal tract during SIV infection in pigtail macaques.

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The ability of human TIM1 to bind phosphatidylethanolamine enhances viral uptake and efferocytosis compared to rhesus and mouse orthologs.

Zhang L, Kitzmiller C, Richard A, Popli S, Choe H bioRxiv. 2024; .

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