Polyunsaturated Fatty Acid Imbalance-A Contributor to SARS CoV-2 Disease Severity

Overview: SARS CoV-2 infection is accompanied by the development of acute inflammation, resolution of which determines the course of infection and its outcome. If not resolved (brought back to preinjury status), the inflamed state progresses to a severe clinical presentation characterized by uncontrolled cytokine release, systemic inflammation, and in some death. In severe CoV-2 disease, the required balance between protective inflammation and its resolution appears missing, suggesting that the ω-3-derived specialized proresolving mediators (SPMs) needed for resolution are either not present or present at ineffective levels compared to competing ω-6 polyunsaturated fatty acid (PUFA) metabolic derivatives. Aim: To determine whether ω-6 PUFA linoleic acid (LA) metabolites increased in those infected with severe disease compared to uninfected controls. Findings: Increased levels of ω-6 LA metabolites, e.g., arachidonic acid (AA), epoxyeicosatrienoic (EET) acid derivatives of AA (8,9-, 11,12-, and 14,15-EETs), AA-derived hydroxyeicosatetraenoic (HETE) acid, dihydroxylated diols (leukotoxin and isoleukotoxin), and prostaglandin E2 with decreased levels of ω-3-derived inflammation resolving SPMs. Therapeutic treatment of SARS CoV-2 patients with ω-3 PUFA significantly increased 18-HEPE (SPM precursor) and EPA-derived diols (11,12- and 14,15-diHETE), while toxic 9,10- and 12,13-diHOMEs (leukotoxin and iosleukotoxin, respectively) decreased. Conclusion: Unbalanced dietary intake of ω-6/ω-3 PUFAs contributed to SARS CoV-2 disease severity by decreasing ω-3-dependent SPM resolution of inflammation and increasing membrane-associated ferroptotic AA peroxidation.