SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition

Peter J Mullen,Arunima Purkayastha,Milica Momcilovic,Ernst W Schmid,Arunachalam Ramaiah,Justin Langerman,David B Shackelford,Robert Damoiseaux,Chandani Sen,Nedas Matulionis,Brigitte N Gomperts,Samuel W French,Kathrin Plath,Gustavo Garcia,Vaithilingaraja Arumugaswami,Heather R Christofk

doi:10.1038/s41467-021-22166-4

Abstract

Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.

Highlights

Viruses hijack host cell metabolism to acquire the building blocks required for replication
The TCA cycle produces metabolites that are used to make amino acids, lipids, and nucleotides[7], which viruses require for replication. mTORC1 is known to regulate anabolic metabolism and mitochondrial activity, and mTORC1 inhibitors can decrease the levels of TCA cycle metabolites[8]
We confirmed the changes in glutamine metabolism in SARS-CoV-2 infected HEK293T cells overexpressing the ACE2 receptor (HEK293T-ACE2): TCA cycle metabolites had decreased labeling of carbons derived from U-13C-glutamine in SARS-CoV-2 infected HEK293T-ACE2 cells (Supplementary Fig. 1i)

Summary

Introduction

Viruses hijack host cell metabolism to acquire the building blocks required for replication. We describe that SARS-CoV-2 infection rewires carbon entry into the TCA cycle, reducing oxidative glutamine metabolism and increasing pyruvate entry via pyruvate carboxylase (PC). We use this information to show that mTORC1 activity is increased during SARS-CoV-2 infection and provide evidence that mTORC1 inhibitors decrease SARS-CoV-2 levels in multiple systems. These data offer a rationale for a potential therapeutic option for treating COVID-19 patients

Methods

Results

Conclusion