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.
Ruofan Wang  1 ,  Camille R Simoneau  2 ,  Jessie Kulsuptrakul  1 ,  Mehdi Bouhaddou  3 ,  Katherine A Travisano  1 ,  Jennifer M Hayashi  4 ,  Jared Carlson-Stevermer  5 ,  James R Zengel  6 ,  Christopher M Richards  6 ,  Parinaz Fozouni  7 ,  Jennifer Oki  5 ,  Lauren Rodriguez  8 ,  Bastian Joehnk  9 ,  Keith Walcott  9 ,  Kevin Holden  5 ,  Anita Sil  9 ,  Jan E Carette  6 ,  Nevan J Krogan  3 ,  Melanie Ott  10 ,  Andreas S Puschnik  11
Affiliations
  • 1. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
  • 2. Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 3. Gladstone Institutes, San Francisco, CA 94158, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 4. Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA.
  • 5. Synthego Corporation, Menlo Park, CA 94025, USA.
  • 6. Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
  • 7. Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 8. UCSF CoLabs, Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 9. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 10. Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute COVID-19 Research Group (QCRG), University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].
  • 11. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: [email protected].
PMID: 33333024 DOI: 10.1016/j.cell.2020.12.004
Abstract

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.