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

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 glycosami nog lycans (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.

Automated summary

The study identified common host factors for three coronaviruses and critical host pathways supporting infection by all of them, including phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis. Inhibition of these pathways reduced replication of all three coronaviruses, while the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. These findings provide important insights for understanding the coronavirus life cycle and developing host-directed therapies.