SARS-CoV-2 infects metabolically-primed epithelial cells in lung cancer models

ABSTRACT

Background: The novel coronavirus SARS-CoV-2 is the cause of the respiratory illness COVID-19—a global pandemic affecting over 4 million individuals worldwide. Viruses efficiently replicate by hijacking host cell machinery to obtain macromolecules and energy by similar mechanisms as cancer cells. Since viral infection is known to alter cellular nutrient requirements, this study explores the metabolites and metabolic pathways associated with SARS-CoV-2 infection. Methods: Bulk and single-cell seequencing data from cell lines and tumor samples were retrieved from publically available datasets. Transcriptional data were retrieved from publically available datasets of gefitinib- and erlotinib-resistant EGFR-mutant cell lines and Calu3 and A549 cells mock treated or infected with SARS-CoV-2. Single-cell RNAseq datasets of EGFR-mutant PC-9 mock and osimertinib treated were downloaded from GEO. 225 metabolites were profiled in CCLE cell lines using LC-MS. Results: To identify metabolic features of cells able to be infected by SARS-CoV-2 via the ACE2 receptor, metabolites associated with ACE2 expression were investigated. ACE2 expression positively correlates with glutamine in upper aerodigestive tract cell lines. Consistent with this, ACE2 expression was examined against a list of 253 metabolism-associated genes and GLUL, which encodes an enzyme (glutamine synthetase) responsible for conversion of glutamate to glutamine, was significantly positively correlated in NSCLC, HNSCC, and SCLC cell lines and confirmed in human tumor datasets. Additionally, GLS, which encodes the enzyme (glutaminase) that catalyzes the opposing reaction, is negatively correlated with ACE2 expression. Further, we analyzed RNA sequencing data from NSCLC cell lines infected with SARS-CoV-2 for 24 hours and revealed that upon infection there is a down regulation of GLUL signifying a metabolic-shift away from glutamine as the cells undergo EMT. Conclusions: We show that SARS-CoV-2 targeting of ACE-2 expressing, metabolically-primed epithelial cells is advantageous to exploit the abundance of glutamine to synthesize nucleotides for rapid replication and viral spread. Legal entity responsible for the study Lauren A. Byers. Funding: NIH/NCI R01-CA207295 (L.A.B.), NIH/NCI U01-CA213273 (L.A.B., J.V.H.), CCSG P30-CA01667 (L.A.B.), University of Texas SPORE in Lung Cancer P5-CA070907 (L.A.B., D.L.G., J.V.H., C.M.G.), the Department of Defense (LC170171;L.A.B.), Khalifa Bin Zayed Al Nahyan Foundation(C.M.G.), The University of Texas MD Anderson Cancer Center-Oropharynx Cancer Program generously supported by Mr. and Mrs. Charles W. Stiefel (F.M.J.), through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program and Andrew Sabin Family Fellowship, and The Rexanna Foundation for Fighting Lung Cancer. Disclosure C. Gay Research grant/Funding (self) AstraZeneca. S. Heeke Honoraria (self) Qiagen;Boehringer Ingelheim;Travel/Accommodation/Expenses Roche. D. Gibbons Advisory/Consultancy, Research grant/Funding (self) AstraZeneca;Janssen;Advisory/Consultancy GlaxoSmithKline;Sanofi;Research grant/Funding (self) Takeda;Ribon Therapeutics;Astellas. J.V. Heymach Advisory/Consultancy, Research grant/Funding (self) AstraZeneca;Advisory/Consultancy Boehringer Ingelheim;EMD Serono;Novartis;Lilly;Hengrui;Guardant Health;GSK;Genentech;Exelixis;Synta;Advisory/Consultancy, Research grant/Funding (self), Licensing/Royalties Spectrum;Research grant/Funding (self) Bayer;GlaxoSmithKline. L.A. Byers Advisory/Consultancy Pfizer;Genentech; Bristol Myers Squibb;Merck;Pharma Mar SA;BergenBio;Advisory/Consultancy, Research grant/Funding (self) Sierra Oncology;GenMab;AstraZeneca;AbbVie;Research grant/Funding (self) Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.