Sheridan Megan A, Yunusov Dinar, Balaraman Velmurugan, Alexenko Andrei P, Yabe Shinichiro, Verjovski-Almeida Sergio, Schust Danny J, Franz Alexander W, Sadovsky Yoel, Ezashi Toshihiko, Roberts R Michael
Bond Life Sciences Center, University of Missouri, Columbia, MO 65211.
Department of Biochemistry, University of Missouri, Columbia, MO 65211.
Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1587-E1596. doi: 10.1073/pnas.1616097114. Epub 2017 Feb 13.
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: ZIKV) 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 (ZIKV). 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.
亚洲谱系寨卡病毒（ZIKV）感染孕妇与婴儿脑部异常有关，但尚不确定人类胚胎在孕期的哪个阶段最易感染该病毒。我们研究了两种模型来探讨人胎盘滋养层细胞对ZIKV的易感性：足月胎盘绒毛来源的细胞滋养层细胞和合胞体滋养层细胞，以及由胚胎干细胞（ESC）分化而来的滋养层细胞集落。后者似乎类似于着床期形成的原始胎盘。足月胎盘来源的细胞能抵抗感染，不表达编码大多数与ZIKV进入相关的附着因子的基因，但表达许多与抗病毒防御相关的基因。相比之下，ESC来源的滋养层细胞具有多种ZIKV进入所需的附着因子，且缺乏强大抗病毒反应系统的组成部分。这些细胞，尤其是集落内的合胞体滋养层区域，在接触低滴度（感染复数>0.07）被认为对胎儿发育影响较小的非洲谱系毒株（MR766乌干达株：ZIKV）后48小时内会迅速被感染，产生传染性病毒并发生裂解。出乎意料的是，对于假定毒性更强的柬埔寨FSS13025株（ZIKV），裂解效应需要显著更高的滴度。我们的数据表明，在成熟绒毛滋养层的保护区域建立之前，发育中的胎儿在孕早期可能最易感染ZIKV。此外，MR766对原始滋养层具有高度嗜性，这可能使受感染母亲的早期胚胎面临被破坏的高风险。
