Serum Levels of Proinflammatory Lipid Mediators and Specialized Proresolving Molecules Are Increased in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 and Correlate With Markers of the Adaptive Immune Response

Abstract

Background: Specialized proresolution molecules (SPMs) halt the transition to chronic pathogenic inflammation. We aimed to quantify serum levels of pro- and anti-inflammatory bioactive lipids in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, and to identify potential relationships with innate responses and clinical outcome.

Methods: Serum from 50 hospital admitted inpatients (22 female, 28 male) with confirmed symptomatic SARS-CoV-2 infection and 94 age- and sex-matched controls collected prior to the pandemic (SARS-CoV-2 negative), were processed for quantification of bioactive lipids and anti-nucleocapsid and anti-spike quantitative binding assays.

Results: SARS-CoV-2 serum had significantly higher concentrations of omega-6-derived proinflammatory lipids and omega-6- and omega-3-derived SPMs, compared to the age- and sex-matched SARS-CoV-2-negative group, which were not markedly altered by age or sex. There were significant positive correlations between SPMs, proinflammatory bioactive lipids, and anti-spike antibody binding. Levels of some SPMs were significantly higher in patients with an anti-spike antibody value >0.5. Levels of linoleic acid and 5,6-dihydroxy-8Z,11Z,14Z-eicosatrienoic acid were significantly lower in SARS-CoV-2 patients who died.

Conclusions: SARS-CoV-2 infection was associated with increased levels of SPMs and other pro- and anti-inflammatory bioactive lipids, supporting the future investigation of the underlying enzymatic pathways, which may inform the development of novel treatments.

Keywords: SARS-CoV-2; anti-nucleocapsid; bioactive lipids; immune response; specialized proresolving molecules.

Figure 1.

A, Partial least square discrimination analysis for the 44 serum lipids quantified in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; n = 50) and age- and sex-matched controls (n = 94) with R² = 0.944, Q² = 0.932, and accuracy = 1.0. B, variable importance in projection (VIP) scores showing important lipid mediators (n = 22, VIP >1.0) involved in differentiation of the 2 groups (control vs SARS-CoV-2). C–J, Histograms of the highest-ranked lipid mediators, omega-3 polyunsaturated fatty acids (PUFAs; EPA, DHA), specialized proresolving molecules (17-HDHA, RvD4, LXA4, LXA5), omega-6 PUFAs (AA, LA), PGD2, HETEs (5-HETE, 9-HETE, 16-HETE, 19-HETE, 15-HETE), 11,12-EET, DiHETEs (5, 15-DiHETEs, 8, 9-DiHETEs), and endocannabinoids (2-AG, AEA). Lipid clusters are based on previously reported analysis [34]. Abbreviations: 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; AEA, N-arachidonoylethanolamine; COVID-19, coronavirus disease 2019; DHA, docosahexaenoic acid; DHET, dihydroxyeicosatrienoic acid; DiHETE, dihydroxyeicosatetraenoic acid; EC, endocannabinoids; EET, epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; LA, linoleic acid; LXA4, Lipoxin A4; PGD2, prostaglandin D2; RvD4, resolvin D4; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SPM, specialized proresolving molecules; VIP, variable importance in projection.

Figure 2.

Serum concentrations of docosahexaenoic acid (DHA; A), 17-hydroxydocosahexaenoic acid (17-HDHA; B), resolvin D4 (RvD4; C), maresin 2 (MaR2; D), and 18-hydroxyeicosapentaenoic acid (18-HEPE; E) in severe acute respiratory syndrome coronavirus 2 (n = 50) and age- and sex-matched control sera (n = 94), stratified by age group. Groups were assessed for normal distribution using D’Agostino–Pearson test. Significance was assessed using Kruskal–Wallis test correcting for multiple comparisons using Dunn test. ∗P ≤ .05, ∗∗P ≤ .01, ∗∗∗P ≤ .001, ∗∗∗∗P ≤ .0001.

Figure 3.

Correlation analysis of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and relevant downstream specialized proresolving molecule pathway metabolites 17-hydroxydocosahexaenoic acid (17-HDHA; A), 14-hydroxydocosahexaenoic acid (14-HDHA; B), and 18-hydroxyeicosapentaenoic acid (18-HEPE; C) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; n = 50) and age- and sex-matched controls (n = 94). Data analyzed by Spearman ρ.

Figure 4.

Correlation analysis between arachidonic acid (AA) and downstream cytochrome P450 metabolites 5,6 epoxyeicosatrienoic acid (EET; A), 8,9-EET (B), 1,12-EET (C), and 14,15-EET (D) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and control groups. Data analyzed by Spearman ρ.

Figure 5.

Serum concentration of significantly altered proresolution lipid mediators eicosapentaenoic acid (EPA; A), 18-hydroxyeicosapentaenoic acid (18-HEPE; B), docosahexaenoic acid (DHA; C), 17-hydroxydocosahexaenoic acid (17-HDHA; D), 14-hydroxydocosahexaenoic acid (14-HDHA; E), resolvin D4 (RvD4; F), maresin 2 (G), and 14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET; H) based on the anti-spike antibody response (low group <0.5, n = 26; high group >0.5, n = 24) in patients with severe acute respiratory syndrome coronavirus 2. Groups were assessed for normal distribution using D’Agostino–Pearson test. Significance was assessed using Mann–Whitney test. ∗P ≤ .05, ∗∗P ≤ .01, ∗∗∗∗P ≤ .0001.