Abstract

Zika Virus Vulnerability and the Strain Differences in Trophoblasts From Pluripotent Stem Cells

Toshihiko Ezashi, Research Associate Professor, The University of Missouri

The early stages of human placental development are not well understood, especially when embryo implants and primitive trophoblasts invade uterus to form primary villi.  As many pregnancy complications, including early embryonic loss, preeclampsia, virus infections, and xenobiotic exposures appear to originate at this stage, models are desperately needed to study the molecular and cellular mechanisms controlling early placenta formation.  In vitro trophoblast models from human pluripotent stem cells (hPSC) are now well established and provide valuable insights into the human trophoblast during the first trimester of pregnancy, which has been largely inaccessible to researchers. The risk of fetal microcephaly by Zika virus (ZIKV) infection is also associated with pregnancy in the first trimester.  As consistent with the clinical observations, trophoblasts derived from hPSC, which represent the early stage of placental structure, are readily infected by ZIKV, whereas trophoblasts from term placental villi are highly resistant.  This represents the fetus’ susceptibility to ZIKV changes over gestation and higher vulnerability which takes place in the early stage.  The study with two genetically distinct ZIKV strains of African and Asian lineage showed a counterintuitive result that African strains were more cytopathic than Asian strains, which are implicated in fetal microcephaly. Although Asian strains were infectious and replicate similarly to African strains, the former was significantly less lytic.  The less destructive Asian ZIKV may lead to fetal infection by allowing the pregnancy to continue and develop complications, while pregnancy infected by the African strain would terminate without the mother’s recognition.  The trophoblasts derived from hPSC can be a valuable model for studying implantation and those events associated with trophoblast specification and their functions.  It also provides a means for screening for pathogens, drugs, and xenobiotics as suspected threats to the conceptus.