Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens Aedes aegypti

PROVIDER: GSE125520 | GEO | 2019/04/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Discovery of Drug Candidates that Inhibit and Eliminate Zika Virus Infection in Fetal and Adult Brain

Project description:Zika virus (ZIKV) infects fetal and adult human brains, and is associated with serious neurological complications including microcephaly and Guillain-Barré Syndrome (GBS). To date, no prophylactic or therapeutic treatment is available to prevent or treat ZIKV infection. Here, we performed a high content chemical screen using a library containing FDA-approved drugs or drug candidates. Two compounds, hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ), were discovered to inhibit ZIKV infection in human cortical neuron progenitor cells (hNPCs). HH was further validated to inhibit ZIKV infection and to rescue ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ suppressed ZIKV infection in adult mouse brain in vivo. Strikingly, HH and AQ fully rescued the severe limb paralysis syndrome developed in ZIKV infected adult mice. This study identifies drug candidates for treatment of ZIKV infection and ZIKV-related neurological complications in fetal and adult patients.

2017-07-06 | GSE89334 | GEO

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

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) 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

2016-08-23 | E-GEOD-80434 | biostudies-arrayexpress

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

Project description:We and others have demonstrated Zika virus (ZIKV) congenital infection evades double-stranded RNA detection, and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. We used orthogonal approaches to test the hypothesis that ZIKV disrupts placental miRNAs to enable viral persistence and fetal pathogenesis. In primary human trophoblasts, high-throughput sequencing crosslinking and immunoprecipitation (AGO-HITS-CLIP) demonstrated an unexpected disruption of placental miRNA-regulated TGF-β networks. In gnotobiotic mice, absence of microbes rendered normally resistant mice susceptible to congenital ZIKV infection, and placental spatial transcriptomics revealed distinct microenvironments defined by significant upregulation of complement cascade components. Finally, treatment of ZIKV-infected mice with the RNAi-enhancer enoxacin led to loss of ZIKV placental persistence and rescue of fetal growth restriction. These results collectively suggest that ZIKV co-opts miRNA inflammatory regulatory networks to persist in the placenta reservoir, a conduit of vertical transmission and fetal pathogenesis.

2023-06-03 | GSE205631 | GEO

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

2023-06-03 | GSE205609 | GEO

Enoxacin shows a broad-spectrum antiviral activity against diverse viruses by enhancing antiviral RNAi in insects

Project description:RNA interference (RNAi) functions as the major host antiviral defense in insects, while less is understood about how to utilize antiviral RNAi in controlling viral infection in insects. Enoxacin belongs to the family of synthetic antibacterial compounds based on a fluoroquinolone skeleton that has been previously found to enhance RNAi in mammalian cells. In this study, we showed that enoxacin efficiently inhibited viral replication of Drosophila C virus (DCV) and Cricket paralysis virus (CrPV) in cultured Drosophila cells. Enoxacin promoted the loading of Dicer-2-processed virus-derived siRNA into the RNA-induced silencing complex, thereby enhancing antiviral RNAi response in infected cells. Moreover, enoxacin treatment elicited an RNAi-dependent in vivo protective efficacy against DCV or CrPV challenge in adult fruit flies. In addition, enoxacin also inhibited replication of flaviviruses, including Dengue virus and Zika virus, in Aedes mosquito cells in an RNAi-dependent manner. Together, our findings demonstrated that enoxacin can enhance RNAi in insects, and enhancing RNAi by enoxacin is an effective antiviral strategy against diverse viruses in insects, which may be exploited as a broad-spectrum antiviral agent to control vector transmission of arboviruses or viral diseases in insect farming.

2021-11-22 | GSE189204 | 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

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

Alphavirus infection triggers antiviral RNAi immunity in mammals

Project description:RNA interference (RNAi) functions as an antiviral immune response in plants and invertebrates, whereas mammalian RNAi response has been found so far only in undifferentiated cells and in differentiated cells inactive in interferon (IFN) system or in infections with viruses disabling viral suppressors of RNAi (VSRs), thereby leading to question the physiological importance of the RNAi pathway in mammals. Here, we identified that wild-type Semliki Forest virus (SFV), a prototypic alphavirus, triggered the Dicer-dependent production of abundant viral (v)siRNAs in different mammalian somatic cells in the presence of VSR. These vsiRNAs were produced from viral dsRNA replicative intermediates, almost exclusively located at the 5’ termini of the viral genome, and loaded into AGO, and they were fully active in slicing cognate viral RNAs. Besides, Sindbis virus, another alphavirus, also induced vsiRNA generation in mammalian somatic cells. AGO2 deficiency increased SFV and SINV replication, while enoxacin, a known RNAi enhancer that functions at post steps of siRNA production, efficiently reduced viral replication. The nucleotide sequence at the 5’ termini of SFV and SINV genome is conserved among the Old World alphaviruses, and mutating the conserved sequences resulted in the recombinant SFV being deficient in vsiRNA production and irresponsive to antiviral RNAi. SFV infection also enabled the production of abundant vsiRNAs and antiviral RNAi in IFN-competent adult mice, and importantly, enhanced RNAi by enoxacin protected adult mice from lethal SFV challenge and reduced the virus-induced neuropathogenesis in the central neuron system. Overall, our findings provide evidence that mammalian antiviral RNAi is active in differentiated cells and adult mice with intact IFN response even in the presence of VSR and present a therapeutic strategy against alphaviruses that include many important emerging and reemerging human pathogens.

2022-10-04 | GSE214453 | GEO

Transcriptional changes during naturally-acquired ZIKA Virus infection render dendritic cells highly conducive to viral replication

Project description:Although dendritic cells (DCs) are among the human cell population best equipped for cell-intrinsic antiviral immune defense, they seem highly susceptible to infection with Zika Virus (ZIKV). Using highly-purified mDC isolated from individuals with naturally-acquired acute infection, we here show that ZIKV induces profound perturbations of transcriptional signatures relative to uninfected patients. Interestingly, we noted a remarkable downregulation of antiviral Interferon-stimulated genes and innate immune sensors, suggesting that ZIKV can actively suppress Interferon-dependent immune responses. In contrast, several host factors known to support ZIKV infection were strongly upregulated during natural ZIKV infection; these transcripts included AXL, the main entry receptor for ZIKV, SOCS3, a negative regulator of ISG expression, and IDO-1, a recognized inducer of regulatory T cell responses. Thus, during in vivo infection, ZIKV can transform the transcriptome of dendritic cells in favor of the virus to render these cells highly conducive to ZIKV infection.

2017-12-18 | GSE101878 | GEO

Zika virus infection activates cellular immune responses in Sertoli cells and dysregulates proteins involved in carbohydrate metabolism and cardiovascular disease

Project description:Zika virus (ZIKV) causes congenital brain abnormalities and Guillain-Barre syndrome. It mainly transmits by Aedes mosquitoes, but infections also are linked to sexual transmissions. ZIKV can proliferate in human Sertoli cells (HSerC) for several weeks in vitro, suggesting that it might be a reservoir for persistent ZIKV infection. This study determined the proteomic changes in HSerC during ZIKV infections by TMT-mass spectrometry analysis. In Sertoli cells, a total of 4416 unique proteins were significantly dis-regulated across 3, 5, and 7 days after ZIKV infection. The dis-regulated proteins include enzymes, transcription regulators, transporters, kinases, peptidases, transmembrane receptors, cytokines, ion channels, and growth factors. Many of those proteins are involved in antiviral response, antigen presentation, and immune cell activation.

2022-01-04 | MSV000088634 | MassIVE

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data