AI Summary
Zika virus infection during pregnancy poses a threat to fetal health, but little is known about its effects on placental trophoblast progenitor cells. This study shows that human trophoblast stem cells (hTSCs) are susceptible to Zika virus infection, and resistance to the virus increases as the cells differentiate. The study also found that the expression of certain genes and the absence of interferon-stimulated genes contribute to the high sensitivity of hTSCs to Zika virus. Zika virus infection disrupts the structure of mature hTSC-derived trophoblast organoids and inhibits syncytialization, which may lead to a preeclampsia phenotype.
Zika virus (ZIKV) infection during pregnancy threatens pregnancy and fetal health. However, the infectivity and pathological effects of ZIKV on placental trophoblast progenitor cells in early human embryos remain largely unknown. Here, using human trophoblast stem cells (hTSCs), we demonstrated that hTSCs were permissive to ZIKV infection, and resistance to ZIKV increased with hTSC differentiation. Combining gene knockout and transcriptome analysis, we demonstrated that the intrinsic expression of AXL and TIM-1, and the absence of potent interferon (IFN)-stimulated genes (ISGs) and IFNs contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived trophoblast organoid (hTSC-organoid), we demonstrated that ZIKV infection disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Single-cell RNA sequencing (scRNA-seq) further demonstrated that ZIKV infection of hTSC-organoids disrupted the stemness of hTSCs and the proliferation of cytotrophoblast cells (CTBs) and probably led to a preeclampsia (PE) phenotype. Overall, our results clearly demonstrate that hTSCs represent the major target cells of ZIKV, and a reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepen our understanding of the characteristics and consequences of ZIKV infection of hTSCs in early human embryos.
Zika virus (ZIKV), a positive-strand RNA arbovirus of the Flaviviridae family, has been reported to be autochthonously transmitted in more than 80 countries worldwide<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref"