SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication

Yuchen Zhang,Hardik Shah,Benjamin E Gewurz,Steven J Elledge,Shuting Zhang,Rui Guo,Deborah T Hung,Vamsi K Mootha,Ying Fang,Jin Hua Liang,Colin N O’ Leary,Matteo Gentili,Sharon H Kim

doi:10.1038/s41467-021-21903-z

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.

Highlights

The recently identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic
Robust production of viral genomic RNA and nucleocapsid protein (Np) was evident by 8 h post-infection in most cells (Fig. 1b and Supplementary Fig. 1a), consistent with prior estimates of the “eclipse period” time from SARS-CoV adsorption to release of infectious progeny[11]
Surprisingly few changes were observed in the abundances of mRNAs encoding metabolic enzymes (Fig. 1c and Table S1), despite a global decrease in host mRNAs in SARS-CoV-2-infected cells (Fig. 1d)

Summary

Introduction

The recently identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. The SARS-CoV-2 replication/transcription complex synthesizes ~30 kilobase viral genomes and highly abundant subgenomic RNAs that serve as templates for viral structural proteins.

Results

Conclusion