Cutting Edge: Severe SARS-CoV-2 Infection in Humans Is Defined by a Shift in the Serum Lipidome, Resulting in Dysregulation of Eicosanoid Immune Mediators

Abstract

The COVID-19 pandemic has affected more than 20 million people worldwide, with mortality exceeding 800,000 patients. Risk factors associated with severe disease and mortality include advanced age, hypertension, diabetes, and obesity. Each of these risk factors pathologically disrupts the lipidome, including immunomodulatory eicosanoid and docosanoid lipid mediators (LMs). We hypothesized that dysregulation of LMs may be a defining feature of the severity of COVID-19. By examining LMs and polyunsaturated fatty acid precursor lipids in serum from hospitalized COVID-19 patients, we demonstrate that moderate and severe disease are separated by specific differences in abundance of immune-regulatory and proinflammatory LMs. This difference in LM balance corresponded with decreased LM products of ALOX12 and COX2 and an increase LMs products of ALOX5 and cytochrome p450. Given the important immune-regulatory role of LMs, these data provide mechanistic insight into an immunolipidomic imbalance in severe COVID-19.

Group IIA Secreted Phospholipase A2 Plays a Central Role in the Pathobiology of COVID-19

“…Given growing evidence suggesting that lipid metabolism plays a critical role in determining COVID-19 outcomes, we sought to identify molecular mechanisms that reconcile key lipidomic changes. Untargeted lipidomic analysis in this study, consistent with other reports, suggest that PLA 2 activation and mitochondrial dysfunction are central determinants of COVID-19 severity and mortality 14,15,22,23 . Specifically, significant elevations in lyso-PLs (PE, PS, but not PC) and increased linoleic and oleic acid levels are hallmarks of catalysis by a sPLA 2 isoform.…”

Skin imprints to provide noninvasive metabolic profiling of COVID-19 patients

“…Among other lipid species, phosphatidylserines were cited as decreased metabolites in COVID-19 5,10,11,13 . Four previous studies reported reduced levels of PS in COVID-19 cases 5,11 , even when mild 10 , moderate and severe 13 cases were compared to controls, on both blood-derived samples 5,10,13 and naso-oropharyngeal swabs 11 , corroborating our findings. PS is a negatively-charged membrane phospholipid that may translocate from inner to outer cell membrane layer in early stages of viral infection 24,25 .…”

Regulation of Tissue Inflammation by 12-Lipoxygenases

“…Another recent study in which lipid mediators were analyzed from sera obtained from SARS-CoV-2-infected patients and healthy controls found that increased PUFA containing lipids were increased in infected patients, and this PUFA pattern was exacerbated with increasing COVID-19 disease severity. Moderate and severe disease was characterized by higher levels of 5-HETE and 12-HETE, suggesting that PUFA metabolites and, in particular, the 12-LOXs may play a paramount role in COVID-19 infection [ 136 ]. These data suggest a clear role in the systemic lipid biomolecule network in the pathogenesis of COVID-19.…”