tetano
Editor, Senior Moderator
[h=1]AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses[/h]
[h=2]Significance[/h] Zika virus (ZIKV) causes microcephaly, whereas other related pathogenic flaviviruses do not. To reach the fetal brain, a virus must be transported from the maternal to the fetal circulation, which requires crossing of the placental barrier. Our studies demonstrate that mammalian cell-derived ZIKV, but not two other globally relevant flaviviruses, efficiently infects fetal endothelial cells, a key component of the placental barrier, because only ZIKV can efficiently use the cell-surface receptor AXL. These data suggest that use of AXL allows ZIKV to enter the fetal bloodstream to gain access to other fetal tissues. Thus, this study provides insight into the unique properties of ZIKV that contribute to its ability to cause microcephaly and other congenital infections and diseases.
[h=2]Abstract[/h] 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.
http://www.pnas.org/content/early/2017/01/31/1620558114
- Audrey St?phanie Richard[SUP]a[/SUP],[SUP]1[/SUP],
- Byoung-Shik Shim[SUP]a[/SUP],[SUP]1[/SUP],
- Young-Chan Kwon[SUP]a[/SUP],
- Rong Zhang[SUP]b[/SUP],[SUP]c[/SUP],[SUP]d[/SUP],[SUP]e[/SUP],
- Yuka Otsuka[SUP]a[/SUP],
- Kimberly Schmitt[SUP]a[/SUP],
- Fatma Berri[SUP]a[/SUP],
- Michael S. Diamond[SUP]b[/SUP],[SUP]c[/SUP],[SUP]d[/SUP],[SUP]e[/SUP], and
- Hyeryun Choe[SUP]a[/SUP],[SUP]2[/SUP]
- Edited by Eric O. Freed, National Cancer Institute, Frederick, MD, and accepted by Editorial Board Member Diane E. Griffin January 5, 2017 (received for review December 14, 2016)
[h=2]Significance[/h] Zika virus (ZIKV) causes microcephaly, whereas other related pathogenic flaviviruses do not. To reach the fetal brain, a virus must be transported from the maternal to the fetal circulation, which requires crossing of the placental barrier. Our studies demonstrate that mammalian cell-derived ZIKV, but not two other globally relevant flaviviruses, efficiently infects fetal endothelial cells, a key component of the placental barrier, because only ZIKV can efficiently use the cell-surface receptor AXL. These data suggest that use of AXL allows ZIKV to enter the fetal bloodstream to gain access to other fetal tissues. Thus, this study provides insight into the unique properties of ZIKV that contribute to its ability to cause microcephaly and other congenital infections and diseases.
[h=2]Abstract[/h] 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.
http://www.pnas.org/content/early/2017/01/31/1620558114