#Genome-wide #CRISPR #screen for #Zika virus #resistance in #human #neural cells (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

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

Yun Li, Julien Muffat, Attya Omer Javed, Heather R. Keys, Tenzin Lungjangwa, Irene Bosch, Mehreen Khan, Maria C. Virgilio, Lee Gehrke, David M. Sabatini, and Rudolf Jaenisch

PNAS first published April 24, 2019 / DOI: https://doi.org/10.1073/pnas.1900867116

Contributed by Rudolf Jaenisch, March 7, 2019 (sent for review January 17, 2019; reviewed by Kristen J. Brennand and Thijn R. Brummelkamp)

 

Significance

Zika virus (ZIKV) is a neurotropic and neurovirulent arbovirus that has severe detrimental impact on the developing human fetal brain. We used a genome-wide CRISPR-Cas9 knockout screen to identify ZIKV host genes in human neural progenitors. The screen identified host factors involved in heparan sulfation, endocytosis, endoplasmic reticulum processing, Golgi function, and interferon activity. Our findings provide insights into host-dependent mechanisms for ZIKV infection in the highly vulnerable human neural progenitor cells and identify molecular targets for potential therapeutic intervention.

 

Abstract

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.

Zika virus – neural progenitors – CRISPR screen – fetal CNS infection – human pluripotent stem cells

 

Footnotes

1 Y.L., J.M., A.O.J., and H.R.K. contributed equally to this work.

2 Present addresses: E25Bio Inc., The Engine, Cambridge, MA 02139; and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

3 Present address: Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109.

4 To whom correspondence should be addressed. Email: jaenisch@wi.mit.edu.

Author contributions: Y.L., J.M., H.R.K., D.M.S., and R.J. designed research; Y.L., J.M., A.O.J., H.R.K., T.L., M.K., and M.C.V. performed research; I.B., L.G., and D.M.S. contributed new reagents/analytic tools; Y.L., J.M., A.O.J., and H.R.K. analyzed data; and Y.L., J.M., A.O.J., H.R.K., and R.J. wrote the paper.

Reviewers: K.J.B., Icahn School of Medicine at Mount Sinai; and T.R.B., Netherlands Cancer Institute.

Conflict of interest statement: R.J. is a cofounder of Fate Therapeutics, Fulcrum Therapeutics and Omega Therapeutics. I.B. and L.G. are cofounders of E25Bio, Inc.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1900867116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Zika Virus; Viral pathogenesis.

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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.