Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses

Cell. 2021 Jan 7;184(1):106-119.e14. doi: 10.1016/j.cell.2020.12.004. Epub 2020 Dec 9.


The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.

Keywords: 229E; COVID-19; CRISPR; OC43; SARS-CoV-2; coronavirus; genetic screen; host factors; host-targeted antivirals; virus-host interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Biosynthetic Pathways / drug effects
  • COVID-19 / genetics*
  • COVID-19 / virology
  • Cell Line
  • Chlorocebus aethiops
  • Cholesterol / biosynthesis
  • Cholesterol / metabolism
  • Cluster Analysis
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Common Cold / genetics
  • Common Cold / virology
  • Coronavirus / classification
  • Coronavirus / physiology*
  • Coronavirus Infections / genetics*
  • Coronavirus Infections / virology
  • Gene Knockout Techniques
  • Genome-Wide Association Study*
  • Host-Pathogen Interactions* / drug effects
  • Humans
  • Mice
  • Phosphatidylinositols / biosynthesis
  • SARS-CoV-2 / physiology*
  • Vero Cells
  • Virus Internalization / drug effects
  • Virus Replication


  • Phosphatidylinositols
  • Cholesterol