Integrated lipidomic and proteomic profiling reveals metabolic network disruption by SARS-CoV-2 variants

Farley, Scotland E.; Kyle, Jennifer E.; Jahn, Helene; Bramer, Lisa M.; Piehowski, Paul D.; Shepmoes, Athena A.; Kaiser, Brooke L.D.; Williams, Sarai M.; Eder, Josie G.; Schultz, Carsten; Tafesse, Fikadu G.

doi:10.1016/j.jlr.2025.100860

Integrated lipidomic and proteomic profiling reveals metabolic network disruption by SARS-CoV-2 variants

Journal Article · Sat Jul 12 00:00:00 EDT 2025 · Journal of Lipid Research

DOI:https://doi.org/10.1016/j.jlr.2025.100860· OSTI ID:2587153

Farley, Scotland E. ^[1]; Kyle, Jennifer E. ^[2]; ^[1]; ^[3]; ^[3]; Shepmoes, Athena A. ^[3]; Kaiser, Brooke L.D. ^[3]; Williams, Sarai M. ^[3]; Eder, Josie G. ^[3]; Schultz, Carsten ^[1]; ^[1]

Oregon Health & Science University, Portland, OR (United States)
Oregon Health & Science University, Portland, OR (United States); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

The rapid evolution of SARS-CoV-2 has produced myriad viral strains with increasing transmissibility and capacity for immune evasion. While effective vaccination campaigns have reduced the fatalities associated with SARS-CoV-2, infections continue, and a detailed understanding of how this virus manipulates host biochemical pathways remains elusive. We asked both whether the patterns of host lipid rewiring remained consistent across variants and whether the changes in the abundance of lipid classes are related to changes in the expression of the enzymes involved in their biosynthesis. We compared global nontargeted lipidomics on A549-ACE2 cells infected with the delta variant (B.1.617.2), or the omicron (B.1.1.529) variant to our previous results of global nontargeted lipidomics on A549-ACE2 cells infected with the original WA1 strain and further performed quantitative proteomics to assess changes in the host proteome. We found that metabolic rewiring, both on the lipid and the enzymatic level, is remarkably consistent across all three variants. We further mapped changes in the expression of host metabolic enzymes, linking enzyme expression to alterations in the abundance of specific lipids during infection. This analysis identified key proteins related to virus-mediated changes in lipid abundance, including fatty acid synthase (FASN), lysosomal acid lipase (LIPA), and ORMDL, a regulator of sphingolipid biosynthesis. These integrated lipidomic and proteomic experiments shed light on the importance of the complex network of host metabolism networks that support SARS-CoV-2 infection and suggest that lipid metabolism may be a promising avenue for uncovering conserved therapeutic targets.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2587153

Report Number(s):: PNNL-SA--212768

Journal Information:: Journal of Lipid Research, Journal Name: Journal of Lipid Research Journal Issue: 8 Vol. 66; ISSN 0022-2275

Publisher:: Elsevier BVCopyright Statement

Country of Publication:: United States

Language:: English

References (29)

Evolution of the SARS‐CoV‐2 omicron variants BA.1 to BA.5: Implications for immune escape and transmission Shrestha, Lok Bahadur; Foster, Charles; Rawlinson, William Reviews in Medical Virology, Vol. 32, Issue 5 https://doi.org/10.1002/rmv.2381	journal	July 2022
Host-directed therapies for infectious diseases: current status, recent progress, and future prospects Zumla, Alimuddin; Rao, Martin; Wallis, Robert S. The Lancet Infectious Diseases, Vol. 16, Issue 4 https://doi.org/10.1016/S1473-3099(16)00078-5	journal	April 2016
Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study Graham, Mark S.; Sudre, Carole H.; May, Anna The Lancet Public Health, Vol. 6, Issue 5 https://doi.org/10.1016/S2468-2667(21)00055-4	journal	May 2021
Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach Naqvi, Ahmad Abu Turab; Fatima, Kisa; Mohammad, Taj Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1866, Issue 10 https://doi.org/10.1016/j.bbadis.2020.165878	journal	October 2020
Dihydroceramide desaturase 1, the gatekeeper of ceramide induced lipotoxicity Rodriguez-Cuenca, S.; Barbarroja, N.; Vidal-Puig, A. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Vol. 1851, Issue 1 https://doi.org/10.1016/j.bbalip.2014.09.021	journal	January 2015
Proteomic and Metabolomic Characterization of COVID-19 Patient Sera Shen, Bo; Yi, Xiao; Sun, Yaoting Cell, Vol. 182, Issue 1 https://doi.org/10.1016/j.cell.2020.05.032	journal	July 2020
SARS-CoV-2 variant B.1.617 is resistant to bamlanivimab and evades antibodies induced by infection and vaccination Hoffmann, Markus; Hofmann-Winkler, Heike; Krüger, Nadine Cell Reports, Vol. 36, Issue 3 https://doi.org/10.1016/j.celrep.2021.109415	journal	July 2021
The variant gambit: COVID-19’s next move Plante, Jessica A.; Mitchell, Brooke M.; Plante, Kenneth S. Cell Host & Microbe, Vol. 29, Issue 4 https://doi.org/10.1016/j.chom.2021.02.020	journal	April 2021
Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization Wang, Pengfei; Casner, Ryan G.; Nair, Manoj S. Cell Host & Microbe, Vol. 29, Issue 5 https://doi.org/10.1016/j.chom.2021.04.007	journal	May 2021
Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study Finnigan, Lucy E. M.; Cassar, Mark Philip; Koziel, Margaret James eClinicalMedicine, Vol. 59 https://doi.org/10.1016/j.eclinm.2023.101946	journal	May 2023
Orm/ORMDL proteins: Gate guardians and master regulators Davis, Deanna; Kannan, Muthukumar; Wattenberg, Binks Advances in Biological Regulation, Vol. 70 https://doi.org/10.1016/j.jbior.2018.08.002	journal	December 2018
Acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, is controlled by SREBP-2 and affects serum cholesterol levels Hasegawa, Shinya; Noda, Kazuki; Maeda, Akina Molecular Genetics and Metabolism, Vol. 107, Issue 3 https://doi.org/10.1016/j.ymgme.2012.08.017	journal	November 2012
Combined Statistical Analyses of Peptide Intensities and Peptide Occurrences Improves Identification of Significant Peptides from MS-Based Proteomics Data Webb-Robertson, Bobbie-Jo M.; McCue, Lee Ann; Waters, Katrina M. Journal of Proteome Research, Vol. 9, Issue 11 https://doi.org/10.1021/pr1005247	journal	November 2010
A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants Farley, Scotland E.; Kyle, Jennifer E.; Leier, Hans C. Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-022-31097-7	journal	June 2022
Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma Cele, Sandile; Gazy, Inbal; Jackson, Laurelle Nature, Vol. 593, Issue 7857 https://doi.org/10.1038/s41586-021-03471-w	journal	March 2021
Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5 Wang, Qian; Guo, Yicheng; Iketani, Sho Nature, Vol. 608, Issue 7923 https://doi.org/10.1038/s41586-022-05053-w	journal	July 2022
Ceramide synthases at the centre of sphingolipid metabolism and biology Mullen, Thomas D.; Hannun, Yusuf A.; Obeid, Lina M. Biochemical Journal, Vol. 441, Issue 3 https://doi.org/10.1042/BJ20111626	journal	January 2012
Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis Heaton, N. S.; Perera, R.; Berger, K. L. Proceedings of the National Academy of Sciences, Vol. 107, Issue 40 https://doi.org/10.1073/pnas.1010811107	journal	September 2010
FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome Karsai, Gergely; Lone, Museer; Kutalik, Zoltán Journal of Biological Chemistry, Vol. 295, Issue 7 https://doi.org/10.1074/jbc.AC119.011883	journal	February 2020
Mammalian ORMDL Proteins Mediate the Feedback Response in Ceramide Biosynthesis Siow, Deanna L.; Wattenberg, Binks W. Journal of Biological Chemistry, Vol. 287, Issue 48 https://doi.org/10.1074/jbc.C112.404012	journal	November 2012
DAnTE: a statistical tool for quantitative analysis of -omics data Polpitiya, A. D.; Qian, W. -J.; Jaitly, N. Bioinformatics, Vol. 24, Issue 13 https://doi.org/10.1093/bioinformatics/btn217	journal	May 2008
LIQUID: an-open source software for identifying lipids in LC-MS/MS-based lipidomics data Kyle, Jennifer E.; Crowell, Kevin L.; Casey, Cameron P. Bioinformatics, Vol. 33, Issue 11 https://doi.org/10.1093/bioinformatics/btx046	journal	January 2017
LMPD: LIPID MAPS proteome database Cotter, D. Nucleic Acids Research, Vol. 34, Issue 90001 https://doi.org/10.1093/nar/gkj122	journal	January 2006
Purification, characterization and molecular cloning of human hepatic lysosomal acid lipase Ameis, Detlev; Merkel, Martin; Eckerskorn, Christoph European Journal of Biochemistry, Vol. 219, Issue 3 https://doi.org/10.1111/j.1432-1033.1994.tb18572.x	journal	February 1994
Molecular mechanisms of PI4K regulation and their involvement in viral replication McPhail, Jacob A.; Burke, John E. Traffic, Vol. 24, Issue 3 https://doi.org/10.1111/tra.12841	journal	June 2022
Structure, Function, and Evolution of Coronavirus Spike Proteins Li, Fang Annual Review of Virology, Vol. 3, Issue 1 https://doi.org/10.1146/annurev-virology-110615-042301	journal	September 2016
Comparing Individual Means in the Analysis of Variance Tukey, John W. Biometrics, Vol. 5, Issue 2 https://doi.org/10.2307/3001913	journal	June 1949
Serine palmitoyltransferase assembles at ER–mitochondria contact sites Aaltonen, Mari J.; Alecu, Irina; König, Tim Life Science Alliance, Vol. 5, Issue 2 https://doi.org/10.26508/lsa.202101278	journal	November 2021
The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19 Bege, Miklós; Borbás, Anikó Pharmaceutics, Vol. 16, Issue 2 https://doi.org/10.3390/pharmaceutics16020217	journal	February 2024

Similar Records

A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants

Journal Article · Fri Jun 17 00:00:00 EDT 2022 · Nature Communications · OSTI ID:1886312

Defining Lipidomic Responses to Coronavirus Infection

Technical Report · Thu Sep 01 00:00:00 EDT 2022 · OSTI ID:1984685

The DNA glycosylase NEIL2 is protective during SARS-CoV-2 infection

Journal Article · Fri Dec 08 23:00:00 EST 2023 · Nature Communications · OSTI ID:2470867

Related Subjects

SARS-CoV-2
SARS-CoV-2 variants
ceramides
coronavirus
host-virus interaction
lipid metabolism
lipidomics
neutral lipids
proteomics
sphingolipids

Integrated lipidomic and proteomic profiling reveals metabolic network disruption by SARS-CoV-2 variants

Citation Formats

References (29)

Similar Records

Related Subjects