Genome-wide CRISPR screen for Zika virus resistance in human neural cells

Zika virus (ZIKV) is a neurotropic and neurovirulent arbovirus that has severe detrimental impact on the developing human fetal brain. To date, little is known about the factors required for ZIKV infection of human neural cells. We identified ZIKV host genes in human pluripotent stem cell (hPSC)-der...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-05, Vol.116 (19), p.9527-9532
Main Authors: Li, Yun, Muffat, Julien, Javed, Attya Omer, Keys, Heather R., Lungjangwa, Tenzin, Bosch, Irene, Khan, Mehreen, Virgilio, Maria C., Gehrke, Lee, Sabatini, David M., Jaenisch, Rudolf
Format: Article
Language:English
Subjects:
Astrocytes
Astrocytes - metabolism
Astrocytes - pathology
Astrocytes - virology
Biological Sciences
Brain
Cell Line
CRISPR
CRISPR-Cas Systems
Disease resistance
Disease Resistance - genetics
Endocytosis
Endoplasmic reticulum
Female
Fetuses
Genes
Genome-Wide Association Study
Genomes
Golgi apparatus
Humans
Infections
Interferon
Male
Mutation
Neural stem cells
Neural Stem Cells - metabolism
Neural Stem Cells - pathology
Neural Stem Cells - virology
Neurovirulence
Pluripotency
Stem cells
Target recognition
Vector-borne diseases
Virus Replication - genetics
Viruses
Zika virus
Zika Virus - physiology
Zika Virus Infection - genetics
Zika Virus Infection - metabolism
Zika Virus Infection - pathology
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Summary:Zika virus (ZIKV) is a neurotropic and neurovirulent arbovirus that has severe detrimental impact on the developing human fetal brain. To date, little is known about the factors required for ZIKV infection of human neural cells. We identified ZIKV host genes in human pluripotent stem cell (hPSC)-derived neural progenitors (NPs) using a genome-wide CRISPR-Cas9 knockout screen. Mutations of host factors involved in heparan sulfation, endocytosis, endoplasmic reticulum processing, Golgi function, and interferon activity conferred resistance to infection with the Uganda strain of ZIKV and a more recent North American isolate. Host genes essential for ZIKV replication identified in human NPs also provided a low level of protection against ZIKV in isogenic human astrocytes. Our findings provide insights into host-dependent mechanisms for ZIKV infection in the highly vulnerable human NP cells and identify molecular targets for potential therapeutic intervention.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1900867116