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Zika virus impacts extracellular vesicle composition and cellular gene expression in macaque early gestation trophoblasts [miRNA-seq]

ABSTRACT: Zika virus (ZIKV) infection at the maternal-placental interface is associated with adverse pregnancy outcomes including fetal demise and pregnancy loss. To determine how infection impacts placental trophoblasts, we utilized rhesus macaque trophoblast stem cells (TSC) that can be directed to differentiate into early gestation syncytiotrophoblasts (ST) and extravillous trophoblasts (EVT). TSCs and STs, but not EVTs, were highly permissive to productive infection with ZIKV strain DAK AR 41524. The impact of ZIKV on the cellular transcriptome showed that infection of TSCs and STs increased expression of immune related genes, including those involved in type I and type III interferon responses. ZIKV exposure altered extracellular vesicle (EV) protein, mRNA, and miRNA cargo, regardless of productive infection. These findings suggest that early gestation macaque TSCs and STs are permissive to ZIKV infection, and that EV analysis may provide a foundation for identifying non-invasive biomarkers of placental infection in a highly translational model.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE193195 | GEO | 2022/01/10

REPOSITORIES: GEO

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Zika virus impacts extracellular vesicle composition and cellular gene expression in macaque early gestation trophoblasts

Project description:Zika virus (ZIKV) infection at the maternal-placental interface is associated with adverse pregnancy outcomes including fetal demise and pregnancy loss. To determine how infection impacts placental trophoblasts, we utilized rhesus macaque trophoblast stem cells (TSC) that can be differentiated into early gestation syncytiotrophoblasts (ST) and extravillous trophoblasts (EVT). TSCs and STs, but not EVTs, were highly permissive to productive infection with ZIKV strain DAK AR 41524. The impact of ZIKV on the cellular transcriptome showed that infection of TSCs and STs increased expression of immune related genes, including those involved in type I and type III interferon responses. ZIKV exposure altered extracellular vesicle (EV) protein, mRNA, and miRNA cargo, regardless of productive infection. These findings suggest that early gestation macaque TSCs and STs are permissive to ZIKV infection, and that EV analysis may provide a foundation for identifying non-invasive biomarkers of placental infection in a highly translational model.

2022-05-20 | PXD033289 | Pride

Zika virus impacts extracellular vesicle composition and cellular gene expression in macaque early gestation trophoblasts

Project description:Zika virus (ZIKV) infection at the maternal-placental interface is associated with adverse pregnancy outcomes including fetal demise and pregnancy loss. To determine how infection impacts placental trophoblasts, we utilized rhesus macaque trophoblast stem cells (TSC) that can be directed to differentiate into early gestation syncytiotrophoblasts (ST) and extravillous trophoblasts (EVT). TSCs and STs, but not EVTs, were highly permissive to productive infection with ZIKV strain DAK AR 41524. The impact of ZIKV on the cellular transcriptome showed that infection of TSCs and STs increased expression of immune related genes, including those involved in type I and type III interferon responses. ZIKV exposure altered extracellular vesicle (EV) protein, mRNA, and miRNA cargo, regardless of productive infection. These findings suggest that early gestation macaque TSCs and STs are permissive to ZIKV infection, and that EV analysis may provide a foundation for identifying non-invasive biomarkers of placental infection in a highly translational model.

2022-01-01 | GSE185291 | GEO

Rhesus macaque early-gestation trophoblast cells are permissive to Zika virus infection and viral exposure altered extracellular vesicle cargo

Project description:Zika virus (ZIKV) infection of maternal and placental cells at the maternal-fetal interface is associated with a spectrum of adverse pregnancy outcomes including fetal demise and pregnancy loss. Trophoblast cell types that comprise the placenta include cytotrophoblasts, syncytiotrophoblasts (STs), and extravillous trophoblasts (EVTs). To determine which trophoblast cells are permissive to ZIKV and to understand how infection impacts cellular gene expression, we utilized a macaque in vitro trophoblast stem cell (TSC) model. TSCs were derived from primary cytotrophoblasts and represent a proliferative trophoblast that can be differentiated into STs and EVTs. TSCs and ST3Ds (STs grown in suspension) were highly permissive to infection with ZIKV strain DAK AR 41524, whereas EVTs maintained a level of resistance to productive infection. The impact of ZIKV on cellular gene expression was determined by transcriptomic and miRNAome analysis. Infection of TSCs and ST3Ds results in increased expression of immune related genes, including those in the type I and type III interferon response. ZIKV exposure impacts EV protein, mRNA, and miRNA cargo, regardless of productive infection. Altogether, these findings suggest TSCs and STs of the macaque are permissive to ZIKV infection and that EV analysis has the potential to identify ZIKV infection. These findings provide a foundation for further ZIKV study and allow for potential ZIKV infection biomarker identification in a highly translational model.

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Zika virus co-opts miRNA networks to persist in placental microenvironments detected by spatial transcriptomics [visium]

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Zika virus co-opts miRNA networks to persist in placental microenvironments detected by spatial transcriptomics [AGO-HITS-CLIP]

2023-06-03 | GSE205609 | GEO

Novel Model for Vertical Zika Virus Transmission via Decidual Cell-mediated Infection of Anchoring Villi

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Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids

Project description:Zika virus (ZIKV) infection during pregnancy results in an increased risk of spontaneous abortion and vertical transmission across placenta results in severe congenital defects in newborns. While the infectivity and pathological effects of ZIKV on the placental trophoblast progenitor cells in early human embryos remains largely unknown. Here, using the human trophoblast stem cells (hTSCs) isolated from human blastocyst, we showed that hTSCs were permissive to ZIKV infection, while resistance to ZIKV increased with differentiation. Combined CRISPR/Cas9-mediated gene knockout and RNA-seq assays, we demonstrated that the intrinsic expression of AXL and TIM-1, as well as the absence of potent interferon (IFN)-stimulated genes (ISGs), contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived 3 dimensional (3D) placental trophoblast organoid model, we demonstrated that ZIKV infection completely disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Overall, our results clearly demonstrated that hTSCs represented the major target cells of ZIKV, and a possible reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepened our understanding of the characteristics and consequences of ZIKV infection of trophoblast stem cells in early human embryo.

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Project description:Placental immunity is critical for fetal health during pregnancy, as invading pathogens spread from the parental blood to the fetus through this organ. However, inflammatory responses in the placenta can adversely affect both the fetus and the pregnant person, and the balance between protective placental immune response and detrimental inflammation is poorly understood. Extracellular vesicles (EVs) are membrane-enclosed vesicles that play a critical role in placental immunity. EVs produced by placental trophoblasts mediate immune tolerance to the fetus and to the placenta itself, but these EVs can also activate detrimental inflammatory responses. The regulation of these effects is not well-characterized, and the role of trophoblast EVs (tEVs) in the response to infection has yet to be defined. The Gram-positive pathogen Listera monocytogenes (Lm) infects the placenta, serving as a model to study tEV function in this context. We investigated the effect of Lm infection on the production and function of tEVs, using a trophoblast stem cell (TSC) model. We found that tEVs from infected TSCs can induce the production of the pro-inflammatory cytokine TNF-α in recipient cells. Surprisingly, this tEV treatment could confer increased susceptibility to subsequent Lm infection, which has not previously been reported as an effect of EVs. Proteomic analysis and RNA-sequencing revealed that tEVs from infected TSCs had altered cargo compared to those from uninfected TSCs. However, no Lm proteins were detected in tEVs from infected TSCs. Together, these results suggest an immunomodulatory role for tEVs during prenatal infection.

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