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Integrin αvβ5 internalizes Zika virus during neural stem cells infection and is a target for antiviral therapy

ABSTRACT: Integrin αvβ5 internalizes Zika virus during neural stem cells infection and is a target for antiviral therapy

PROVIDER: PRJNA578627 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10316406.fastq.gz	Fastqsanger.gz
	SRR10316407.fastq.gz	Fastqsanger.gz
	SRR10316408.fastq.gz	Fastqsanger.gz

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Integrin αvβ5 internalizes Zika virus during neural stem cells infection and is a target for antiviral therapy

Project description:Here, we performed the first CRISPR-Cas9 genome-wide screen in glioblastoma stem cells (GSCs) to identify factors determining ZIKV neurotropism. Using a ZIKV-ZsGreen reporter virus, a new strategy was developed to sort infection-resistant cells, expand, and enrich the resistant pool. Importantly, bioinformatics analysis and functional validation revealed integrin αvβ5 as an internalization factor for ZIKV. Expression of αvβ5 is correlated with ZIKV susceptibility in various cell lines and matched the cell tropism in developing human cerebral cortex. Blocking antibody against integrin αvβ5 but not αvβ3 efficiently inhibited ZIKV infection. Mechanistic evaluation showed that ZIKV binds to cells but fails to internalize when treated with integrin αvβ5 blocking antibody. αvβ5 directly binds to ZIKV virions, activates FAK (focal adhesion kinase), which is required for ZIKV infection. Strikingly, pharmaceutical inhibitors of αvβ5, SB273005 and cilengitide suppressed ZIKV infection at nanomolar concentrations. Finally, αvβ5 blocking antibody or inhibitors reduced ZIKV infection and alleviated ZIKV induced pathology in human neural stem cells (hNSC) and in mouse brain. This is the first study, to the best of our knowledge, identifying integrin αvβ5 is an internalization factor for ZIKV providing a new therapeutic target as well as two promising drug candidates that potentially can be used as prophylactics or treatments for ZIKV infections.

2020-01-22 | GSE139142 | GEO

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

Zika infected neural stem cells

Project description:Zika infected neural stem cells

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Integrin αvβ5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy.

Project description:We perform a CRISPR-Cas9 genome-wide screen in glioblastoma stem cells and identify integrin αvβ5 as an internalization factor for Zika virus (ZIKV). Expression of αvβ5 is correlated with ZIKV susceptibility in various cells and tropism in developing human cerebral cortex. A blocking antibody against integrin αvβ5, but not αvβ3, efficiently inhibits ZIKV infection. ZIKV binds to cells but fails to internalize when treated with integrin αvβ5-blocking antibody. αvβ5 directly binds to ZIKV virions and activates focal adhesion kinase, which is required for ZIKV infection. Finally, αvβ5 blocking antibody or two inhibitors, SB273005 and cilengitide, reduces ZIKV infection and alleviates ZIKV-induced pathology in human neural stem cells and in mouse brain. Altogether, our findings identify integrin αvβ5 as an internalization factor for ZIKV, providing a promising therapeutic target, as well as two drug candidates for prophylactic use or treatments for ZIKV infections.

| S-EPMC7293422 | biostudies-literature

Differential responses of human fetal brain neural stem cells to Zika virus infection

Project description:Purpose: The goal of this study is to investigate the effect of Zika virus infection on neural stem cells Methods: RNA-Seq transcriptome analysis of neural stem cells infected with Zika virus compared to mock infected

2017-02-17 | GSE93385 | GEO

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

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

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Transcriptome analysis of Zika infected neural stem cells

Project description:RNA-seq was utilized to characterize the transcriptome of human neural stem cells infected with Zika virus strains MR766 and Paraiba at MOI 1. Coding and noncoding genes were analyzed to determine transcriptional changes 3 days post-infection.

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miRNA analysis of Zika infected neural stem cells

Project description:small RNA-seq was utilized to characterize the transcriptome of human neural stem cells infected with Zika virus strains MR766 and Paraiba at MOI 1. Coding and noncoding genes were analyzed to determine transcriptional changes 3 days post-infection.

2019-06-18 | GSE113639 | GEO

AGO-iCLIP-seq analysis of Zika infected neural stem cells

Project description:AGO-iCLIP-seq was utilized to characterize the RNAs bound to AGO in human neural stem cells infected with Zika virus strains Paraiba at MOI 1. miRNAs and mRNAs were analyzed to determine changes in RNAs loaded into the RISC 4 days post-infection.

2019-06-18 | GSE113638 | GEO

Zika Virus Non-Coding RNAs Antagonize Antiviral Responses by PKR-Mediated Translational Arrest (RNA-Seq)

Project description:Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome profiling of infected human cells to show that sfRNAs block translation of antiviral genes. Mechanistically, we demonstrate that specific RNA structures present in sfRNAs trigger PKR activation, which instead of limiting viral replication, enhances viral particle production. Although ZIKV infection induces mRNA expression of antiviral genes, translation efficiency of type I interferon and interferon stimulated genes were significantly downregulated by PKR activation. Our results reveal a novel viral adaptation mechanism mediated by sfRNAs, where ZIKV increases its fitness by repurposing the antiviral role of PKR into a proviral factor.

2024-04-28 | GSE254252 | GEO

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