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

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 outperforms 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.

Whole genome CRISPR screens identify LRRK2-regulated endocytosis as a major mechanism for extracellular tau uptake by human neurons

“…Genes required for uptake of Ebola, influenza A, and Zika viruses were obtained from published CRISPR screens [31][32][33] . Since the Ebola data were also analysed with MAGeCK, we defined genes required for viral uptake using an unadjusted p-value threshold of 0.01; this information was not available for the influenza A and Zika studies, so we defined genes required for viral uptake as having an adjusted p-value < 0.05.…”

Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection

“…Since IAV has a relatively small genome, host machinery is required in order to accomplish the viral life cycle. To uncover host dependency factors that are necessary for IAV replication, numerous large-scale RNA interference (RNAi) screens and genome-wide CRISPR/Cas 9 screen were performed [29,[100][101][102][103]. For instance, SON DNA binding protein was important for IAV virion trafficking in an early infection stage and CDC-like kinase 1 facilitated AIV replication [29].…”

“…USP47 facilitated viral entry, whereas TNFSF12 (APRIL) and TNFSF12-TNFSF13 (TWEPRIL) helped with viral replication [101]. Using genome-wide CRISPR/Cas9 screen, several genes of sialic acid biosynthesis and related glycosylation pathways were involved with H5N1 infection [102], and WDR7, CCDC115, and TMEM199 were essential for viral entry and regulation of V-type ATPase assembly [103]. Furthermore, single-cell transcriptome sequencing (RNA-seq) was applied to explore host-virus interactions, revealing a correlation between defective viral genomes and virus-induced host transcriptional programs [104].…”

The viral protein U (Vpu)-interacting host protein ATP6V0C down-regulates cell-surface expression of tetherin and thereby contributes to HIV-1 release

“…Bafilomycin A1, an inhibitor of V-ATPase activity, binds ATP6V0C and inhibits proton translocation into the lysosomal lumen, thus inhibiting lysosomal acidification and cargo degradation (64). Inhibition of endosomal acidification by bafilomycin A1 abolished the infection of several viruses such as dengue virus (65), Zika virus (66), human papillomavirus (67), rhinovirus (68), equine infectious anemia virus (69), murine leukemia virus (70), and influenza A virus (71)(72)(73).…”