1. SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition.
- Author
-
Mullen PJ, Garcia G Jr, Purkayastha A, Matulionis N, Schmid EW, Momcilovic M, Sen C, Langerman J, Ramaiah A, Shackelford DB, Damoiseaux R, French SW, Plath K, Gomperts BN, Arumugaswami V, and Christofk HR
- Subjects
- Animals, Benzamides pharmacology, Cell Line, Chlorocebus aethiops, Glucose metabolism, Glutamine metabolism, HEK293 Cells, Humans, Lung metabolism, Lung virology, Morpholines pharmacology, Naphthyridines pharmacology, Pyrimidines pharmacology, Pyruvate Carboxylase biosynthesis, SARS-CoV-2 metabolism, Vero Cells, Virus Replication drug effects, COVID-19 pathology, Citric Acid Cycle physiology, Mechanistic Target of Rapamycin Complex 1 antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 1 metabolism, Protein Kinase Inhibitors pharmacology
- 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.
- Published
- 2021
- Full Text
- View/download PDF