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 May 7, 2019 116 (19) 9527-9532; first published April 24, 2019 https://doi.org/10.1073/pnas.1900867116

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

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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.

Footnotes

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

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

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

  • ↵4To whom correspondence should be addressed. Email: jaenisch{at}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.

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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, Rudolf Jaenisch
Proceedings of the National Academy of Sciences May 2019, 116 (19) 9527-9532; DOI: 10.1073/pnas.1900867116
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