Deep phenotyping of the lipidomic response in COVID‐19 and non‐COVID‐19 sepsis

Abstract

BackgroundLipids may influence cellular penetrance by viral pathogens and the immune response that they evoke. We deeply phenotyped the lipidomic response to SARs‐CoV‐2 and compared that with infection with other pathogens in patients admitted with acute respiratory distress syndrome to an intensive care unit (ICU).MethodsMass spectrometry was used to characterise lipids and relate them to proteins, peripheral cell immunotypes and disease severity.ResultsCirculating phospholipases (sPLA2, cPLA2 (PLA2G4A) and PLA2G2D) were elevated on admission in all ICU groups. Cyclooxygenase, lipoxygenase and epoxygenase products of arachidonic acid (AA) were elevated in all ICU groups compared with controls. sPLA2 predicted severity in COVID‐19 and correlated with TxA2, LTE4 and the isoprostane, iPF2α‐III, while PLA2G2D correlated with LTE4. The elevation in PGD2, like PGI2 and 12‐HETE, exhibited relative specificity for COVID‐19 and correlated with sPLA2 and the interleukin‐13 receptor to drive lymphopenia, a marker of disease severity. Pro‐inflammatory eicosanoids remained correlated with severity in COVID‐19 28 days after admission. Amongst non‐COVID ICU patients, elevations in 5‐ and 15‐HETE and 9‐ and 13‐HODE reflected viral rather than bacterial disease. Linoleic acid (LA) binds directly to SARS‐CoV‐2 and both LA and its di‐HOME products reflected disease severity in COVID‐19. In healthy marines, these lipids rose with seroconversion. Eicosanoids linked variably to the peripheral cellular immune response. PGE2, TxA2 and LTE4 correlated with T cell activation, as did PGD2 with non‐B non‐T cell activation. In COVID‐19, LPS stimulated peripheral blood mononuclear cell PGF2α correlated with memory T cells, dendritic and NK cells while LA and DiHOMEs correlated with exhausted T cells. Three high abundance lipids – ChoE 18:3, LPC‐O‐16:0 and PC‐O‐30:0 – were altered specifically in COVID. LPC‐O‐16:0 was strongly correlated with T helper follicular cell activation and all three negatively correlated with multi‐omic inflammatory pathways and disease severity.ConclusionsA broad based lipidomic storm is a predictor of poor prognosis in ARDS. Alterations in sPLA2, PGD2 and 12‐HETE and the high abundance lipids, ChoE 18:3, LPC‐O‐16:0 and PC‐O‐30:0 exhibit relative specificity for COVID‐19 amongst such patients and correlate with the inflammatory response to link to disease severity.

Implementation of multiomic mass spectrometry approaches for the evaluation of human health following environmental exposure

“…The lipidomics data revealed how the lipidome controls the immune response and its effect on sepsis severity depending on the COVID-19 status. Expression of inflammatory hubs responsible for restricting inflammation, such as ChoE-18 : 3, LPC-O-16 : 0, and PC-O-30 : 0, is decreased in patients with sepsis from COVID-19, while expression of inflammatory hubs responsible for enhancing inflammation, such as sPLA2, PGD2, and 12-HETE, is increased in patients with sepsis from COVID-19 as reported by Meng et al 141 Data from a multi-omics approach using proteomics, metabolomics, and lipidomics were applied to build a workflow to predict aggravation of COVID-19 symptoms of patients in the ICU. Two proteins (CCL7 and CA14), as well as one lipid (HexCer 18 : 2; O2/20 : 0), were identified as short-term predictors of worsening COVID-19 progression in ICU patients as described by Kugler et al 142 …”

Prostanoids in Cardiac and Vascular Remodeling

“…Analysis of patients with sepsis revealed that although PGD 2 is elevated in patients with sepsis of bacterial or viral origin, it has a relative selectivity for sepsis induced by SARS-CoV-2. 226 Indeed, genetic deletion or pharmacological inhibition of DPr1 protects aged mice from lethal SARS-CoV-2 infection. 227…”

Differential Impact In Vivo of Pf4-ΔCre–Mediated and Gp1ba-ΔCre–Mediated Depletion of Cyclooxygenase-1 in Platelets in Mice

“…Prostanoids in serum from mice and cell culture media of mouse aortas were measured, as described by Meng et al 15 Blood Loss by Tail Amputation in Hyperlipidemic Mice (Ldlr −/− ) Mice were used in this experiment after feeding a high-fat diet (HFD) for 12 weeks; 2 mm of the tail was amputated using a sterile scalpel under anesthesia with ketamine/xylazine/ acepromazine. Blood was collected into a preweighed glass tube containing Drabkin reagent to estimate the amount of blood loss and hemoglobin content at 420 nm using a microplate reader.…”