Enhanced Production of Lipid Mediators in Plasma and Activation of DNA Damage Pathways in PBMCs Are Correlated With the Severity of Ancestral SARS-CoV-2 Infection

Jeffrey A Tomalka¹, Anna Owings², Michelle Galeas-Pena³, Carly G K Ziegler^{4

5

6

7

8}, Tanya O Robinson², Thomas G Wichman², Hannah Laird², Haley B Williams², Neha S Ghaliwal², Steven Everman², Yousaf Zafar², Jaclyn M L Walsh^{6

9

10}, Alex K Shalek^{4

5

6

7

8

9

11

12

13}, Bruce H Horwitz^{9

10

14}, Jose Ordovas-Montanes^{5

6

9

10

13}, Sarah C Glover³, Yann Gibert^{15

16}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
² Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
³ Department of Medicine, Section of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
⁴ Program in Health Sciences & Technology, Harvard Medical School & MIT, Boston, Massachusetts, USA.
⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁷ Harvard Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, USA.
⁸ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁹ Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
¹¹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹² Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹³ Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
¹⁴ Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
¹⁵ Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
¹⁶ Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi, USA.

PMID: 40322970
PMCID: PMC12904103 (available on 2026-05-15)
DOI: 10.1096/fj.202403195R

Enhanced Production of Lipid Mediators in Plasma and Activation of DNA Damage Pathways in PBMCs Are Correlated With the Severity of Ancestral SARS-CoV-2 Infection

Jeffrey A Tomalka et al. FASEB J. 2025.

. 2025 May 15;39(9):e70600.

doi: 10.1096/fj.202403195R.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
² Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
³ Department of Medicine, Section of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
⁴ Program in Health Sciences & Technology, Harvard Medical School & MIT, Boston, Massachusetts, USA.
⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁷ Harvard Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, USA.
⁸ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁹ Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
¹¹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹² Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹³ Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
¹⁴ Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
¹⁵ Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
¹⁶ Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi, USA.

PMID: 40322970
PMCID: PMC12904103 (available on 2026-05-15)
DOI: 10.1096/fj.202403195R

Abstract

Many questions remain unanswered regarding the implication of genetics and lipid metabolites with severe SARS-CoV-2 infections. We performed bulk RNA-seq and a total fatty acid panel analysis on PBMCs and plasma collected from 10 infected and 10 uninfected patients. Univariate comparison of lipid metabolites using the Mann-Whitney U-test revealed that six lipid metabolites were significantly increased in COVID-19 patients, including the lipid mediators arachidonic acid (AA) and eicosapentaenoic acid (EPA), which both give rise to eicosanoids. Key lipids implicated in inflammation, including AA and EPA, along with the fatty acids DHA and DPA, were significantly and positively correlated to the WHO disease severity score. Analysis of our bulk RNA-seq dataset demonstrated distinct transcriptional profiles leading to a segregation of COVID-19 patients based on the WHO score. Ontology, KEGG, and Reactome analysis identified several key pathways and nodes that were enriched for genes related to innate immunity, interactions between lymphoid and nonlymphoid cells, interleukin signaling, and subsequent DNA damage pathways. EPA levels correlated with heightened cell cycling and DNA damage pathways observed in patients with a high WHO score. We studied gene expression in nasopharyngeal swabs from 58 healthy and COVID-19 participants and identified that genes implicated in eicosanoid synthesis, such as alox5, alox12, and alox15B, were specifically up-regulated in high WHO score patients in several cell types of the nasopharynx, especially goblet cells across different viral variants (Deta and Omicron). Using published nasal scRNA-seq datasets from COVID-19 patients, we evaluated the expression of genes implicated in eicosanoid synthesis, such as ALOX5, ALOX15, and ALOX15B, across nasal cell types and COVID-19 severity groups. Altogether, our study highlights the fact that the increase in specific lipids implicated in inflammation and the genes required for their synthesis correlated with the severity of the SARS-CoV-2 infection.

Keywords: DNA damage; RNAseq; SARS‐CoV‐2; eicosanoids; fatty acid; lipidomics.

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Conflict of interest statement

Declaration of interests

The authors declare no competing interests

Update of

Enhanced production of eicosanoids in plasma and activation of DNA damage pathways in PBMCs are correlated with the severity of ancestral COVID-19 infection.
Tomalka JA, Owings A, Galeas-Pena M, Ziegler CGK, Robinson TO, Wichman TG, Laird H, Williams HB, Dhaliwal NS, Everman S, Zafar Y, Shalek AK, Horwitz BH, Ordovas-Montanes J, Glover SC, Gibert Y. Tomalka JA, et al. medRxiv [Preprint]. 2023 Sep 15:2023.09.14.23295549. doi: 10.1101/2023.09.14.23295549. medRxiv. 2023. Update in: FASEB J. 2025 May 15;39(9):e70600. doi: 10.1096/fj.202403195R. PMID: 37745424 Free PMC article. Updated. Preprint.

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Enhanced Production of Lipid Mediators in Plasma and Activation of DNA Damage Pathways in PBMCs Are Correlated With the Severity of Ancestral SARS-CoV-2 Infection

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Enhanced Production of Lipid Mediators in Plasma and Activation of DNA Damage Pathways in PBMCs Are Correlated With the Severity of Ancestral SARS-CoV-2 Infection

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