Genome-wide CRISPR/Cas9 Screen Identifies Host Factors Essential for Influenza Virus Replication

Julianna Han, Jasmine T. Perez, Cindy Chen, Yan Li, Asiel Benitez, Matheswaran Kandasamy, Yoontae Lee, Jorge Andrade, Benjamin tenOever, Balaji Manicassamy

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

The emergence of influenza A viruses (IAVs) from zoonotic reservoirs poses a great threat to human health. As seasonal vaccines are ineffective against zoonotic strains, and newly transmitted viruses can quickly acquire drug resistance, there remains a need for host-directed therapeutics against IAVs. Here, we performed a genome-scale CRISPR/Cas9 knockout screen in human lung epithelial cells with a human isolate of an avian H5N1 strain. Several genes involved in sialic acid biosynthesis and related glycosylation pathways were highly enriched post-H5N1 selection, including SLC35A1, a sialic acid transporter essential for IAV receptor expression and thus viral entry. Importantly, we have identified capicua (CIC) as a negative regulator of cell-intrinsic immunity, as loss of CIC resulted in heightened antiviral responses and restricted replication of multiple viruses. Therefore, our study demonstrates that the CRISPR/Cas9 system can be utilized for the discovery of host factors critical for the replication of intracellular pathogens. Using a genome-wide CRISPR/Cas9 screen, Han et al. demonstrate that the major hit, the sialic acid transporter SLC35A1, is an essential host factor for IAV entry. In addition, they identify the DNA-binding transcriptional repressor CIC as a negative regulator of cell-intrinsic immunity.

Original languageEnglish
Pages (from-to)596-607
Number of pages12
JournalCell Reports
Volume23
Issue number2
DOIs
StatePublished - 10 Apr 2018

Keywords

  • CIC
  • CRISPR/Cas9 screen
  • Capicua
  • GeCKO
  • H5N1
  • SLC35A1
  • cell-intrinsic immunity
  • host factors
  • influenza virus
  • sialic acid pathway

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