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Nat Commun. 2020 Jan 9;11(1):164. doi: 10.1038/s41467-019-13965-x.

Genome-wide CRISPR screen identifies host dependency factors for influenza A virus infection.

Author information

1
Harvard University Virology Program, Harvfvard Medical School, Boston, MA02142, USA.
2
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA, 02142, USA.
3
Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG, UK.
4
Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, 02115, USA.
5
School of Molecular Cell Biology and Biotechnology, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
6
School of informatics, University of Edinburgh, Edinburgh, EH8 9YL, UK.
7
Center for Cancer Research, Massachusetts General hospital, Harvard Medical School, Boston, MA, USA.
8
The Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA, USA.
9
MRC Center for Inflammation Research, University of Edinburgh, Edinburgh, UK.
10
Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG, UK. j.k.baillie@ed.ac.uk.
11
Intensive Care Unit, Royal Infirmary Edinburgh, Edinburgh, EH16 5SA, UK. j.k.baillie@ed.ac.uk.
12
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA, 02142, USA. nhacohen@mgh.harvard.edu.
13
Massachusetts General Hospital Cancer Center, Boston, MA, 02129, USA. nhacohen@mgh.harvard.edu.

Abstract

Host dependency factors that are required for influenza A virus infection may serve as therapeutic targets as the virus is less likely to bypass them under drug-mediated selection pressure. Previous attempts to identify host factors have produced largely divergent results, with few overlapping hits across different studies. Here, we perform a genome-wide CRISPR/Cas9 screen and devise a new approach, meta-analysis by information content (MAIC) to systematically combine our results with prior evidence for influenza host factors. MAIC out-performs other meta-analysis methods when using our CRISPR screen as validation data. We validate the host factors, WDR7, CCDC115 and TMEM199, demonstrating that these genes are essential for viral entry and regulation of V-type ATPase assembly. We also find that CMTR1, a human mRNA cap methyltransferase, is required for efficient viral cap snatching and regulation of a cell autonomous immune response, and provides synergistic protection with the influenza endonuclease inhibitor Xofluza.

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