SARS-CoV-2 patients exhibit high specialized pro-resolving molecule serum levels

In a recent study posted to the medRxiv* pre-print server, researchers from the UK quantified the levels of specialized pro-resolving molecules (SPMs) and pro-inflammatory bioactive lipids in the serum of in-patients positive for severe acute respiratory syndrome 2 (SARS-CoV-2), and determined its correlation with immune responses and clinical outcomes.

SPMs are known for stimulating and activating endogenous pathways to terminate chronic pathogenic inflammations. Present knowledge on the outcome of SARS-CoV-2 infection on endogenous levels of SPMs and EETs is insufficient. Studying the effect of SARS-CoV-2 infection on the serum profile of these bio-lipids might help develop potential therapeutics which can trigger the SPM resolution pathway in SARS-CoV-2 infections.

The study

In the present study, the researchers compared the serum levels of bioactive lipids in a cohort of 50 (22 female, 28 male) in-patients who had confirmed symptomatic SARS-CoV-2 infection with that of 94 individuals from an age- and sex-matched cohort (control group) collected prior to the pandemic. The researchers used liquid chromatography-mass spectrometry (LC-MS) for extracting and measuring the serum bioactive lipids.

They also aimed to determine the associations between immune responses to SARS-COV-2 infection and serum levels of bioactive lipids through anti-nucleocapsid and anti-spike quantitative binding assays including the enzyme-linked immunoassay (ELISA). Among the SARS-CoV-2 cohort, 30 patients recovered and were discharged, 25 were in the intensive care unit (ICU), and 20 died during the course of the study.

Findings

The comparison of SPM levels revealed high serum levels of ꞷ-6 derived pro-inflammatory lipids and ω-6 and ω-3 derived anti-inflammatory SPM lipids in the SARS-CoV-2 cohort whereas the control cohort displayed very low or undetectable levels of SPMs. The concentration of polyunsaturated fatty acids (PUFAs) in the sera from the SARS-CoV-2 cohort and the control group was almost similar.

Serum levels of the pro-inflammatory molecule (prostaglandin D2) PGD2 and the anti-inflammatory SPMs [17-hydroxy docosahexaenoic acid (17-HDHA), resolvin D4 (RvD4), lipoxin A4 (LXA4), lipoxin A5 (LXA5)], endocannabinoids (2-AG, AEA) and, 11,12-epoxyeicosatrienoic acid (11,12-EET) were significantly high in the SARS-CoV-2 cohort than the control cohort.

Partial least squares discriminant analysis (PLS-DA) displayed a clear separation in serum levels between both the cohorts for three age groups but most of the lipid contributing to this separation was similar for three age groups. This indicated that age has no impact in mounting a pro-resolution response.

Both the cohorts showed a correlation between docosahexaenoic acid (DHA) and the downstream metabolites, 17-HDHA and 14-HDHA. The SARS-CoV-2 cohort displayed a correlation between eicosapentaenoic acid (EPA) and 18-hydroxyeicosapentaenoic acid (18-HEPE), which was absent in the control cohort. This suggests that SARS-CoV-2 infection triggers E series resolving pathways.

The control group had a healthy range of arachidonic acid (AA) in their serum whereas the SARS-CoV-2 cohort exhibited elevated levels of AA in their serum. The ratio of anti-inflammatory EETs and the downstream metabolites [dihydroxy-8Z,11Z,14Z- eicosatrienoic acid (DHETs)] was compared and the ratio of 11,12-EET:11,12-DHET was significantly high in sera from the SARS-CoV-2 cohort as compared to the control cohort. The ratio of 8,9-EET:8,9-DHET and 14,15- 203 EET:14,15-DHET exhibited some differences but was less consistent across different age groups in both cohorts. The levels of AA correlated with all EETs in the SARS-CoV-2 cohort serum while that in the control cohort correlated with 8,9-EET and 11,12-EET. These results indicated a change in flux through the soluble epoxide hydrolase (sEH) pathway by SARS-Cov-2 infection.

To determine the associations between immune responses to SARS-COV-2 infection and serum levels of bioactive lipids, the researchers performed anti-nucleocapsid and anti-spike quantitative binding assays. The assay revealed that variants in the SARS-CoV-2 cohort were either the Hu-1 strain or the variant defining the 20B lineage (defined by the spike D614G variant), with no variation in nucleocapsid amino acid sequence. The SARS-CoV-2 cohort exhibited variation in levels of anti-nucleocapsid and anti-spike antibody ranging between 0.15 to 3.11 and 0.115-3.067, respectively.

According to the range of anti-spike antibody binding patients were classified into two groups: low (<0.5, n=26) and high (>0.5, n=26).  The patients who died in the SARS-CoV-2 cohort represented low levels of anti-spike antibody binding. The levels of 18-HEPE, 17-HDHA, RvD4, and 14, 15-EET were significantly high in patients having anti-spike antibody binding value >0.5. Overall, these results indicated a positive correlation between these bioactive lipids and anti-spike antibody binding among the SARS-CoV-2 cohort.

Conclusion

The analysis of the association between the serum level of bioactive lipids and its clinical outcome revealed significantly low levels of LA and 5,6-DHET in patients who died, while the ratio of 5,6-EET:5,6-DHET among the SARS-CoV-2 cohort was high in patients who died in comparison to those who survived.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Susha Cheriyedath

Susha has a Bachelor of Science (B.Sc.) degree in Chemistry and Master of Science (M.Sc) degree in Biochemistry from the University of Calicut, India. She always had a keen interest in medical and health science. As part of her masters degree, she specialized in Biochemistry, with an emphasis on Microbiology, Physiology, Biotechnology, and Nutrition. In her spare time, she loves to cook up a storm in the kitchen with her super-messy baking experiments.