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Molecular Signatures Associated with ZIKV Exposure in Human Cortical Neural Progenitors and Astrocytes

ABSTRACT: Zika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function remains elusive. Here we systematically profiled transcriptomes of human neural progenitor cells (hNPCs) and astrocytes exposed to Asian ZIKVC, African ZIKVM, and Dengue virus (DENV). DENV causes distinct gene expression changes; and ZIKV has a broader impact on the expression of gene involved in DNA replication and repair. While overall expression profiles are similar, ZIKVC, but not ZIKVM, induces upregulation of viral response genes. Upon ZIKV infection, astrocytes exhibit more prominent transcriptome changes than hNPCs, particularly enriching genes related to inflammatory response and cytokine production pathways. Our analyses reveal cell-type- and strain-specific molecular signatures associated with ZIKV infection, and identify astrocytes as a major direct target of ZIKV. Further investigation of ZIKV-host interactions based our transcriptomic datasets may help to illuminate neural virulence determinants of ZIKV in patients. Gene Expression Analyses of the cells infected with different flaviviruses

ORGANISM(S): Homo sapiens

SUBMITTER: Peng Jin

PROVIDER: E-GEOD-80434 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Molecular Signatures Associated with ZIKV Exposure in Human Cortical Neural Progenitors

Project description:Zika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function remains elusive. Here we systematically profiled transcriptomes of human neural progenitor cells (hNPCs) exposed to Asian ZIKVC, African ZIKVM, and Dengue virus (DENV). DENV causes distinct gene expression changes; and ZIKV has a broader impact on the expression of gene involved in DNA replication and repair. While overall expression profiles are similar, ZIKVC, but not ZIKVM, induces upregulation of viral response genes. Our analyses reveal virus- and strain-specific molecular signatures associated with ZIKV infection. Further investigation of ZIKV-host interactions based our transcriptomic datasets may help to illuminate neural virulence determinants of ZIKV in patients.

2016-08-23 | GSE80434 | GEO

RNA sequencing of Aedes mosquitoes infected with Zika virus (ZIKV) or Dengue virus (DENV)

Project description:Zika virus (ZIKV), a pathogen of global health concern, is transmitted to humans by Aedes mosquitoes. However, the molecular interactions between the vector and the virus remain largely unexplored. We demonstrated that ZIKV and dengue virus (DENV) have similar tropism and infection kinetics in two mosquito strains with different degrees of susceptibility to infection. Comparison of Aedes aegypti’s molecular responses to ZIKV and DENV infection indicated that around 40% of the mosquito’s infection-responsive transcriptome is virus-specific. Regulated genes also included key factors of the mosquito’s anti-viral immunity, pointing to the possible involvement of the Toll innate immune pathway. Comparison of ZIKV and DENV infection-responsive transcriptome data to those for yellow fever virus and West Nile virus identified 26 genes likely to play key roles in virus infection of Aedes mosquitoes. Through reverse genetic analyses, we showed that the Toll and the Jak/Stat innate immune pathways mediate increased resistance to ZIKV infection, and the virus use vATPase and inosine-5’-monophosphate dehydrogenase as mosquito’s host factors.

2017-11-07 | GSE96605 | GEO

Proteomic changes of ZIKV and DENV in iPS-derived neurospheres

Project description:Brain abnormalities and congenital malformations have been linked to the circulating strain of Zika virus (ZIKV) in Brazil since 2016 during the microcephaly outbreak; however, the molecular mechanisms behind several of these alterations and differential viral molecular targets have not been fully elucidated. Here we explore the proteomic alterations induced by ZIKV by comparing the Brazilian (Br ZIKV) and the African (MR766) viral strains, in addition to comparing them to the molecular responses to the Dengue virus (DENV). Neural stem cells (NSCs) derived from induced pluripotent stem (iPSCs) were cultured both as monolayers and in suspension (resulting in neurospheres), which were then infected with ZIKV (Br ZIKV or ZIKV MR766) or DENV to assess alterations within neural cells. Large-scale proteomic analyses allowed the comparison not only between viral strains but also regarding the two- and three-dimensional cellular models of neural cells derived from iPSCs, and the effects on their interaction. Altered pathways and biological processes were observed, related to cell death, cell cycle dysregulation, and neurogenesis. These results reinforce already published data and provide further information regarding the biological alterations induced by ZIKV and DENV.

2022-06-29 | PXD026909 | Pride

ZIKV prevents host mRNA export from the nucleus by disrupting UPF1 function

Project description:Zika virus (ZIKV) is a mosquito-borne virus that can have dramatic neurodevelopmental consequences when infection occurs in utero. Previous studies demonstrated that ZIKV downregulates the master regulator of nonsense mediated decay, UPF1. To examine whether this process contributes to disruption of neural development, we investigated the effect of ZIKV infection on UPF1 interaction with host RNA in neural progenitor cells. Here, we show that ZIKV-mediated disruption of UPF1 function in neural progenitor cells causes retention of mRNA in the nucleus, resulting in decreased protein levels of specific transcripts involved in neural differentiation.

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Proteomic changes of ZIKV strains and DENV in neural stem cells

2022-06-29 | PXD026825 | Pride

Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids

Project description:The re-emergence of Zika virus (ZIKV) in the Western Hemisphere has resulted in global public health crisis since 2015. ZIKV preferentially infects and targets human neural progenitor cells (hNPCs) and causes fetal microcephaly upon maternal infection. hNPCs not only play critical roles during fetal brain development, but also persist in adult brain throughout life. Yet the mechanism of innate antiviral immunity in hNPCs remains largely unknown. Here, we show that ZIKV infection triggers the abundant production of virus-derived small interfering RNAs in hNPCs, but not in the more differentiated progenies or somatic cells. Ablation of key RNAi machinery components significantly enhances ZIKV replication in hNPCs. Furthermore, enoxacin, a broad-spectrum antibiotic that is known as an RNAi enhancer, exerts potent anti-ZIKV activity in hNPCs and other RNAi-competent cells. Strikingly, enoxacin treatment completely prevents ZIKV infection and circumvents ZIKV-induced microcephalic phenotypes in brain organoid models that recapitulate human fetal brain development. Our findings highlight the physiological importance of RNAi-mediated antiviral immunity during the early stage of human brain development, uncovering a novel strategy to combat human congenital viral infections through enhancing RNAi.

2019-04-15 | GSE125520 | GEO

Effect of ZIKV on pre-implantation embryos

Project description:To determine the effect of Zika virus infection on pre-implantation embryonic development, we performed single blastocyst RNA-Seq on MOCK and ZIKV infected embryos. ZIKV infection results in an increased risk of spontaneous abortion and poor intrauterine growth although the mechanisms underlying fetal loss remain undetermined. Little is known about the impact of ZIKV infection during the earliest stages of pregnancy, or pre- and peri-implantation, because most current studies of ZIKV infection in pregnancy models focus on post-implantation stages. Here, we demonstrate that trophectoderm cells of pre-implantation human and mouse embryos can be efficiently infected with ZIKV, and that trophectoderm can propagate virus causing cell death of neural progenitors. These findings were corroborated by our demonstration that hESC-derived trophectoderm cells are infected by ZIKV in a dose dependent manner. RNAseq of single blastocysts revealed key transcriptional changes in cellular and physiologic functions upon ZIKV infection, including nervous system development and function, prior to commitment to the neural cell lineage. Finally, the pregnancy rate of mice infected pre-implantation was > 50% lower than females infected at E4.5. These results demonstrate that pre-implantation ZIKV infection of trophectoderm leads to miscarriage or spontaneous abortion. Moreover, pre- and peri-implantation ZIKV infects trophectoderm cells that propagate virus over time causing cell death in neural progenitors. Cumulatively, these data demonstrate that vertical pre- and peri-implantation ZIKV infection of trophectoderm impairs fetal development and causes neural progenitor cell death, elucidating a previously unappreciated association of pre- and peri-implantation ZIKV infection and microcephaly.

2019-08-16 | GSE133254 | GEO

Salivary glands from Aedes aegypti infected with DENV, ZIKV, and CHIKV

Project description:Aedes aegypti mosquitoes were orally infected with DENV, ZIKV or CHIKV virus, and once virus infection reached salivary gland tissues, these glands were dissected out and i-TRAQ performed to identify differentially expressed proteins during virus infection.

2021-06-02 | MSV000087564 | MassIVE

Transcriptional and Translational Dynamics of Zika and Dengue Virus Infection

Project description:Zika virus (ZIKV) and dengue virus (DENV) are members of the Flaviviridae family of RNA viruses and cause severe disease in humans. ZIKV and DENV share over 90% of their genome sequences, however the clinical features of Zika and dengue infections are very different reflecting tropism and cellular effects. Here, we used simultaneous RNA sequencing and ribosome footprinting to define the transcriptional and translational dynamics of ZIKV and DENV infection in human neuronal progenitor cells (hNPCs). The gene expression data showed induction of aminoacyl tRNA synthetases (ARS) and the translation-activating PIM1 kinase indicating an increase in RNA translation capacity. The data also reveal activation of different cell stress reponses, with ZIKV triggering a BACH1/2 redox program, and DENV activating the ETF/CHOP endoplasmatic reticulum (ER) stress program. The RNA translation data highlight activation of polyamine metabolism through changes in key enzymes and their regulators. This pathway is needed for eIF5A hypusination and has been implicated viral translation and replication. Concerning the viral RNA genomes, ribosome occupancy readily identifies highly translated open reading frames and a novel upstream ORF (uORF) in the DENV genome. Together, our data highlight both the cellular stress response and also the activation of RNA translation and polyamine metabolism during DENV and ZIKV infection.

2022-07-06 | GSE207347 | GEO

Zika Virus Targets Human Cortical Neural Precursors and Attenuates Their Growth

Project description:The suspected link between infection by Zika virus (ZIKV), a re-emerging flavivirus, and microcephaly, is an urgent global health concern. The direct target cells of ZIKV in developing human fetuses are not clear. Here we show that ZIKV serially passaged in monkey and mosquito cell lines infects human induced pluripotent stem cells (hiPSCs)-derived cortical neural progenitor cells (hNPCs) with much higher efficiency compared to hiPSCs and hNPC-derived immature cortical neurons. Infected hNPCs produces infectious ZIKV particles. Importantly, ZIKV infection increases cell death and dysregulates cell cycle progression, resulted in attenuated hNPC growth. RNA-sequencing analysis of infected hNPCs further reveals transcriptional dysregulation, notably genes in cell cycle pathways. Our results identify human cortical neural precursors as a major and direct target of ZIKV infection and establish a tractable experimental model system to investigate the impact and mechanism of ZIKV on human brain development and a platform to screen therapeutic compounds.

2016-03-04 | GSE78711 | GEO

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