Zika virus alters DNA methylation status of genes involved in Hippo signaling pathway in human neural progenitor cells

Aim: This study was aimed to understand if Zika virus (ZIKV) alters the DNA methylome of human neural progenitor cells (hNPCs). Materials & methods: Whole genome DNA methylation profiling was performed using human methylationEPIC array in control and ZIKV infected hNPCs. Results & conclusion: ZIKV infection altered the DNA methylation of several genes such as WWTR1 (TAZ) and RASSF1 of Hippo signaling pathway which regulates organ size during brain development, and decreased the expression of several centrosomal-related microcephaly genes, and genes involved in stemness and differentiation in human neural progenitor cells. Overall, ZIKV downregulated the Hippo signaling pathway genes which perturb the stemness and differentiation process in hNPCs, which could form the basis for ZIKV-induced microcephaly.

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In Vitro Zika Virus Infection of Human Neural Progenitor Cells: Meta-Analysis of RNA-Seq Assays

Microorganisms ◽

10.3390/microorganisms8020270 ◽

2020 ◽

Vol 8 (2) ◽

pp. 270 ◽

Cited By ~ 3

Author(s):

Rossella Gratton ◽

Paola Maura Tricarico ◽

Almerinda Agrelli ◽

Heverton Valentim Colaço da Silva ◽

Lucas Coêlho Bernardo ◽

...

Keyword(s):

Progenitor Cells ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Meta Analysis ◽

Fetal Brain ◽

Neural Progenitor ◽

Gene Expression Omnibus ◽

Human Neural Progenitor Cells ◽

Apoptosis Pathways

The Zika virus (ZIKV) is an emergent arthropod-borne virus (arbovirus) responsible for congenital Zika syndrome (CZS) and a range of other congenital malformations. Evidence shows that ZIKV infects human neural progenitor cells (hNPCs) in the fetal brain, prompting inflammation and tissue damage/loss. Despite recent advances, little is known about the pathways involved in CZS pathogenesis. We performed a meta-analysis, gene ontology (GO), and pathway analysis of whole transcriptome studies with the aim of clarifying the genes and pathways potentially altered during hNPCs infection with ZIKV. We selected three studies (17 samples of infected hPNCs compared to hPNCs uninfected controls) through a systematic search of the Gene Expression Omnibus (GEO) database. The raw reads were trimmed, counted, and normalized. Next, we performed a rank product meta-analysis to detect consistently differentially expressed genes (DEGs) in these independent experiments. We detected 13 statistically significant DEGs. GO ontology and reactome analysis showed an enrichment of interferon, pro-inflammatory, and chemokines signaling and apoptosis pathways in ZIKV-infected cells. Moreover, we detected three possible new candidate genes involved in hNPCs infection: APOL6, XAF1, and TNFRSF1. Our results confirm that interferon (IFN) signaling dominates the ZIKV response, and that a crucial contribution is given by apoptotic pathways, which might elicit the CZS phenotype.

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Heparin prevents Zika virus induced-cytopathic effects in human neural progenitor cells

Antiviral Research ◽

10.1016/j.antiviral.2016.12.023 ◽

2017 ◽

Vol 140 ◽

pp. 13-17 ◽

Cited By ~ 36

Author(s):

Silvia Ghezzi ◽

Lynsay Cooper ◽

Alicia Rubio ◽

Isabel Pagani ◽

Maria Rosaria Capobianchi ◽

...

Keyword(s):

Progenitor Cells ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Cytopathic Effects ◽

Human Neural Progenitor Cells

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Non-Structural Protein 5 of Zika Virus Interacts with p53 in Human Neural Progenitor Cells and Induces p53-Mediated Apoptosis

Virologica Sinica ◽

10.1007/s12250-021-00422-7 ◽

2021 ◽

Author(s):

Ping Li ◽

Hualian Jiang ◽

Hong Peng ◽

Weijie Zeng ◽

Yongheng Zhong ◽

...

Keyword(s):

Progenitor Cells ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Structural Protein ◽

Human Neural Progenitor Cells

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Zika virus differentially infects human neural progenitor cells according to their state of differentiation and dysregulates neurogenesis through the Notch pathway

Emerging Microbes & Infections ◽

10.1080/22221751.2019.1637283 ◽

2019 ◽

Vol 8 (1) ◽

pp. 1003-1016 ◽

Cited By ~ 21

Author(s):

Pauline Ferraris ◽

Marielle Cochet ◽

Rodolphe Hamel ◽

Ivan Gladwyn-Ng ◽

Christian Alfano ◽

...

Keyword(s):

Progenitor Cells ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Notch Pathway ◽

Neural Progenitor ◽

Human Neural Progenitor Cells

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Zika virus infection induces mitosis abnormalities and apoptotic cell death of human neural progenitor cells

Scientific Reports ◽

10.1038/srep39775 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 91

Author(s):

Bruno S. F. Souza ◽

Gabriela L. A. Sampaio ◽

Ciro S. Pereira ◽

Gubio S. Campos ◽

Silvia I. Sardi ◽

...

Keyword(s):

Cell Death ◽

Virus Infection ◽

Progenitor Cells ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Apoptotic Cell ◽

Neural Progenitor ◽

Apoptotic Cell Death ◽

Zika Virus Infection ◽

Human Neural Progenitor Cells

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Zika Virus Induces Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL)-Mediated Apoptosis in Human Neural Progenitor Cells

Cells ◽

10.3390/cells9112487 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2487

Author(s):

Jae Kyung Lee ◽

Ji-Ae Kim ◽

Soo-Jin Oh ◽

Eun-Woo Lee ◽

Ok Sarah Shin

Keyword(s):

Cell Death ◽

Tumor Necrosis Factor ◽

Progenitor Cells ◽

Zika Virus ◽

Tumor Necrosis ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Cytopathic Effects ◽

Human Neural Progenitor Cells ◽

Necrosis Factor

Zika virus (ZIKV) remains as a public health threat due to the congenital birth defects the virus causes following infection of pregnant women. Congenital microcephaly is among the neurodevelopmental disorders the virus can cause in newborns, and this defect has been associated with ZIKV-mediated cytopathic effects in human neural progenitor cells (hNPCs). In this study, we investigated the cellular changes that occur in hNPCs in response to ZIKV (African and Asian lineages)-induced cytopathic effects. Transmission electron microscopy showed the progress of cell death as well as the formation of numerous vacuoles in the cytoplasm of ZIKV-infected hNPCs. Infection with both African and Asian lineages of ZIKV induced apoptosis, as demonstrated by the increased activation of caspase 3/7, 8, and 9. Increased levels of proinflammatory cytokines and chemokines (IL-6, IL-8, IL-1β) were also detected in ZIKV-infected hNPCs, while z-VAD-fmk-induced inhibition of cell death suppressed ZIKV-mediated cytokine production in a dose-dependent manner. ZIKV-infected hNPCs also displayed significantly elevated gene expression levels of the pro-apoptotic Bcl2-mediated family, in particular, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Furthermore, TRAIL signaling led to augmented ZIKV-mediated cell death and the knockdown of TRAIL-mediated signaling adaptor, FADD, resulted in enhanced ZIKV replication. In conclusion, our findings provide cellular insights into the cytopathic effects induced by ZIKV infection of hNPCs.

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