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.
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CIC, CRISPR/Cas9 screen, Capicua, GeCKO, H5N1, SLC35A1, cell-intrinsic immunity, host factors, influenza virus, sialic acid pathway, A549 Cells, CRISPR-Cas Systems, Gene Knockout Techniques, Gene Library, Genome, Human, Humans, Influenza A Virus, H5N1 Subtype, Lentivirus, Nucleotide Transport Proteins, Virus Internalization, Virus Replication