SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication
Yuchen Zhang, Rui Guo, Sharon H. Kim, Hardik Shah, Shuting Zhang, Jin Hua Liang, Yīng Fāng, Matteo Gentili, Colin N. O’ Leary, Steven J. Elledge, Deborah T. Hung, Vamsi K. Mootha, Benjamin E. Gewurz
Abstract
The recently identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. How this novel beta-coronavirus virus, and coronaviruses more generally, alter cellular metabolism to support massive production of ~30 kB viral genomes and subgenomic viral RNAs remains largely unknown. To gain insights, transcriptional and metabolomic analyses are performed 8 hours after SARS-CoV-2 infection, an early timepoint where the viral lifecycle is completed but prior to overt effects on host cell growth or survival. Here, we show that SARS-CoV-2 remodels host folate and one-carbon metabolism at the post-transcriptional level to support de novo purine synthesis, bypassing viral shutoff of host translation. Intracellular glucose and folate are depleted in SARS-CoV-2-infected cells, and viral replication is exquisitely sensitive to inhibitors of folate and one-carbon metabolism, notably methotrexate. Host metabolism targeted therapy could add to the armamentarium against future coronavirus outbreaks.