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Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1587-E1596. doi: 10.1073/pnas.1616097114. Epub 2017 Feb 13.

Vulnerability of primitive human placental trophoblast to Zika virus.

Author information

1
Bond Life Sciences Center, University of Missouri, Columbia, MO 65211.
2
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
3
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brazil.
4
Laboratory of Gene Expression, Instituto Butantan, 05503-900 São Paulo, SP, Brazil.
5
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211.
6
Division of Animal Sciences, University of Missouri, Columbia, MO 65211.
7
Department of Obstetrics, Gynecology, and Women's Health, University of Missouri, Columbia, MO 65211.
8
Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213.
9
Bond Life Sciences Center, University of Missouri, Columbia, MO 65211; robertsrm@missouri.edu.

Abstract

Infection of pregnant women by Asian lineage strains of Zika virus (ZIKV) has been linked to brain abnormalities in their infants, yet it is uncertain when during pregnancy the human conceptus is most vulnerable to the virus. We have examined two models to study susceptibility of human placental trophoblast to ZIKV: cytotrophoblast and syncytiotrophoblast derived from placental villi at term and colonies of trophoblast differentiated from embryonic stem cells (ESC). The latter appear to be analogous to the primitive placenta formed during implantation. The cells from term placentas, which resist infection, do not express genes encoding most attachment factors implicated in ZIKV entry but do express many genes associated with antiviral defense. By contrast, the ESC-derived trophoblasts possess a wide range of attachment factors for ZIKV entry and lack components of a robust antiviral response system. These cells, particularly areas of syncytiotrophoblast within the colonies, quickly become infected, produce infectious virus and undergo lysis within 48 h after exposure to low titers (multiplicity of infection > 0.07) of an African lineage strain (MR766 Uganda: ZIKVU) considered to be benign with regards to effects on fetal development. Unexpectedly, lytic effects required significantly higher titers of the presumed more virulent FSS13025 Cambodia (ZIKVC). Our data suggest that the developing fetus might be most vulnerable to ZIKV early in the first trimester before a protective zone of mature villous trophoblast has been established. Additionally, MR766 is highly trophic toward primitive trophoblast, which may put the early conceptus of an infected mother at high risk for destruction.

KEYWORDS:

Zika virus; embryonic stem cell; placenta; pregnancy; trophoblast

PMID:
28193876
PMCID:
PMC5338554
DOI:
10.1073/pnas.1616097114
[Indexed for MEDLINE]
Free PMC Article

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