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

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

doi:10.1038/s41467-021-22166-4

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

Nat Commun. 2021 Mar 25;12(1):1876. doi: 10.1038/s41467-021-22166-4.

Authors

Peter J Mullen¹, Gustavo Garcia Jr², Arunima Purkayastha³, Nedas Matulionis¹, Ernst W Schmid¹, Milica Momcilovic⁴, Chandani Sen³, Justin Langerman¹, Arunachalam Ramaiah⁵, David B Shackelford^{4

6}, Robert Damoiseaux^{2

6

7

8

9}, Samuel W French^{6

10}, Kathrin Plath^{1

4

6

9

11}, Brigitte N Gomperts^{3

4

6

9

11}, Vaithilingaraja Arumugaswami^{2

6}, Heather R Christofk^{12

13

14}

Affiliations

¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
² Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
³ UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
⁴ Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
⁵ Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, CA, USA.
⁶ Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
⁷ California Nanosystems Institute, UCLA, Los Angeles, CA, USA.
⁸ Department of Bioengineering, UCLA Samueli School of Engineering, Los Angeles, CA, USA.
⁹ Department of Molecular Biology Interdepartmental Program, UCLA, Los Angeles, CA, USA.
¹⁰ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
¹¹ Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA.
¹² Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. [email protected].
¹³ Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA. [email protected].
¹⁴ Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Benzamides / pharmacology
COVID-19 / pathology*
Cell Line
Chlorocebus aethiops
Citric Acid Cycle / physiology*
Glucose / metabolism
Glutamine / metabolism
HEK293 Cells
Humans
Lung / metabolism
Lung / virology
Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Morpholines / pharmacology
Naphthyridines / pharmacology
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / pharmacology
Pyruvate Carboxylase / biosynthesis
SARS-CoV-2 / metabolism
Vero Cells
Virus Replication / drug effects

Substances

9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one
Benzamides
Morpholines
Naphthyridines
Protein Kinase Inhibitors
Pyrimidines
vistusertib
Glutamine
Mechanistic Target of Rapamycin Complex 1
Pyruvate Carboxylase
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding