W154 - Severe Ancestral COVID-19 Leads to Enhanced Inflammatory Lipids Production in Plasma, Activation of DNA Damage Pathways in Pbmcs, and Upregulation of Eicosinoid Synthesis Genes in the Nasopharyngeal Mucosa

Anna Owings, DO – Fellow, Medicine/Digestive Diseases, University of Mississippi Medical Center; Jeff Tomalka, PhD – Assistant Professor, Department of Pathology and Laboratory Medicine and Emory Vaccine Center, Emory School of Medicine; Carly Ziegler – student, MD-PhD Program, Harvard Medical School; Tanya Robinson, PhD – Assistant Professor, Medicine/Digestive Diseases, University of Mississippi Medical Center; Thomas Wichman, BS – medical student, Medicine, University of Mississippi Medical Center; Hannah Laird, BS – medical student, School of Medicine, University of Mississippi Medical Center; Haley Williams, BS – medical student, School of Medicine, University of Mississippi Medical Center; Neha Dhaliwal, MS – research associate, Medicine/Digestive D, University of Mississippi Medical Center; Spurthi Tarugu, MD – fellow, Medicine/Digestive Diseases, University of Mississippi Medical Center; Alex Shalek, PhD – Professor, Massachusetts Institue of Technology; Bruce Horwitz, MD – Associate Professor, Division of GI/Nutrition, Boston Children's Hospital; Jose Ordovas-Montanes, PhD – Research Faculty, Gastroenterology, Boston Children's Hospital; Yann Gibert, PhD – Associate Professor, Cell & Molecular Biology, University of Mississippi Medical Center

Abstract Text: The impact of severe SARS-COV-2 infection on lipid metabolism is not fully understood. To further explore this question, we performed total fatty acid analysis on plasma and bulk RNA-seq on PBMCs from 10 individuals infected with ancestral SARS-COV-2 and 10 age and disease matched uninfected participants. We compared this data with our ancestral SARS-COV-2 nasopharyngeal (NP) sc-RNA-seq dataset (Cell. 2021 Sep 2;184(18):4713-4733.). Univariate analysis between groups (Mann-Whitney U-test) demonstrated that six (6) lipids were significantly increased in SARS-CoV-2 participant plasma. These included the inflammatory lipids, Arachidonic Acid (AA) and Eicosapentaenoic Acid (EPA) which are both key contributors to eicosanoid production. AA, EPA, and the fatty acids, DHA and DPA, significantly correlated with WHO disease severity score in infected participants. When stratified by WHO score, heatmap analysis of bulk RNA-seq data from PBMCs demonstrated distinct transcriptional profiles. Ontology, KEGG and Reactome analysis identified several key pathways and nodes which were enriched for genes related to innate immunity, interactions between lymphoid and nonlymphoid cells and interleukin signaling. EPA message correlated with heightened cell cycling and DNA damage pathways in participants with WHO score >5. Furthermore, our ancestral SARS-COV-2 NP sc-RNA-seq dataset revealed that genes implicated in eicosanoid synthesis including alox5, alox12 and alox15B were up-regulated in NP cells including goblet cells, particularly in individuals with WHO score >5. Our study demonstrates that specific inflammatory lipids including EPA activate DNA damage pathways in PBMCs and lead to upregulation of eicosanoid synthesis genes at the mucosal surface in the nasopharynx in severe COVID-19 infection.