Genome-wide screening identifies unique host-directed drugs and pro-viral signalling pathways for SARS-CoV-2

SARS-CoV-2 is a positive-sense RNA virus that was responsible for the devastating COVID-19 pandemic. Although the current disease burden is less severe, there are limited treatment options, and a looming threat of the emergence of variants and future pandemics. To address these challenges, we performed genome-wide CRISPR knockout screens in a novel human lung cell line NCI-H23 ACE2 , as well as in HEK293T ACE2 cells, with SARS-CoV-2 Wuhan strain, and identified several host-dependency factors including NRAS, KAT5, HTR3E and GNL3L. Drugs targeting some of these dependency factors, donepezil, dH-ergocristine, trametinib and sorafenib, showed effective pan-coronaviral inhibition in cell lines. Trametinib also showed inhibition of SARS-CoV-2 Delta variant in primary human airway tissue model (ALI). We also demonstrate that SARS-CoV-2 inhibits IFN-β induction through an NRAS/Raf/MEK/ERK signaling pathway dependent mechanism. Our study highlights the efficiency of a bilateral approach of gene silencing and antiviral screening to identify host-dependency factors and effective antivirals.