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J Virol. 2019 Jul 30;93(16). pii: e00211-19. doi: 10.1128/JVI.00211-19. Print 2019 Aug 15.

A CRISPR Activation Screen Identifies Genes That Protect against Zika Virus Infection.

Author information

1
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
2
RNA Bioinformatics and High-Throughput Analysis, Friedrich Schiller University, Jena, Germany.
3
European Virus Bioinformatics Center, Jena, Germany.
4
Centre of Pathophysiology Toulouse Purpan, INSERM U1043, CNRS UMR5282, Toulouse III University, Toulouse, France.
5
Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany.
6
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California, USA.
7
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel sklan@tauex.tau.ac.il.
#
Contributed equally

Abstract

Zika virus (ZIKV) is an arthropod-borne emerging pathogen causing febrile illness. ZIKV is associated Guillain-Barré syndrome and other neurological complications. Infection during pregnancy is associated with pregnancy complications and developmental and neurological abnormalities collectively defined as congenital Zika syndrome. There is still no vaccine or specific treatment for ZIKV infection. To identify host factors that can rescue cells from ZIKV infection, we used a genome-scale CRISPR activation screen. Our highly ranking hits included a short list of interferon-stimulated genes (ISGs) previously reported to have antiviral activity. Validation of the screen results highlighted interferon lambda 2 (IFN-λ2) and interferon alpha-inducible protein 6 (IFI6) as genes providing high levels of protection from ZIKV. Activation of these genes had an effect on an early stage in viral infection. In addition, infected cells expressing single guide RNAs (sgRNAs) for both of these genes displayed lower levels of cell death than did the controls. Furthermore, the identified genes were significantly induced in ZIKV-infected placenta explants. Thus, these results highlight a set of ISGs directly relevant for rescuing cells from ZIKV infection or its associated cell death and substantiate CRISPR activation screens as a tool to identify host factors impeding pathogen infection.IMPORTANCE Zika virus (ZIKV) is an emerging vector-borne pathogen causing a febrile disease. ZIKV infection might also trigger Guillain-Barré syndrome, neuropathy, and myelitis. Vertical transmission of ZIKV can cause fetus demise, stillbirth, or severe congenital abnormalities and neurological complications. There is no vaccine or specific antiviral treatment against ZIKV. We used a genome-wide CRISPR activation screen, where genes are activated from their native promoters to identify host cell factors that protect cells from ZIKV infection or associated cell death. The results provide a better understanding of key host factors that protect cells from ZIKV infection and might assist in identifying novel antiviral targets.

KEYWORDS:

CRISPR activation; Zika virus; genome-wide screen; interferon-stimulated genes; interferons

PMID:
31142663
PMCID:
PMC6675891
[Available on 2020-01-30]
DOI:
10.1128/JVI.00211-19

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