Plasmalogen Loss in Sepsis and SARS-CoV-2 Infection

Abstract

Plasmalogens are plasma-borne antioxidant phospholipid species that provide protection as cellular lipid components during cellular oxidative stress. In this study we investigated plasma plasmalogen levels in human sepsis as well as in rodent models of infection. In humans, levels of multiple plasmenylethanolamine molecular species were decreased in septic patient plasma compared to control subject plasma as well as an age-aligned control subject cohort. Additionally, lysoplasmenylcholine levels were significantly decreased in septic patients compared to the control cohorts. In contrast, plasma diacyl phosphatidylethanolamine and phosphatidylcholine levels were elevated in septic patients. Lipid changes were also determined in rats subjected to cecal slurry sepsis. Plasma plasmenylcholine, plasmenylethanolamine, and lysoplasmenylcholine levels were decreased while diacyl phosphatidylethanolamine levels were increased in septic rats compared to control treated rats. Kidney levels of lysoplasmenylcholine as well as plasmenylethanolamine molecular species were decreased in septic rats. Interestingly, liver plasmenylcholine and plasmenylethanolamine levels were increased in septic rats. Since COVID-19 is associated with sepsis-like acute respiratory distress syndrome and oxidative stress, plasmalogen levels were also determined in a mouse model of COVID-19 (intranasal inoculation of K18 mice with SARS-CoV-2). 3 days following infection, lung infection was confirmed as well as cytokine expression in the lung. Multiple molecular species of lung plasmenylcholine and plasmenylethanolamine were decreased in infected mice. In contrast, the predominant lung phospholipid, dipalmitoyl phosphatidylcholine, was not decreased following SARS-CoV-2 infection. Additionally total plasmenylcholine levels were decreased in the plasma of SARS-CoV-2 infected mice. Collectively, these data demonstrate the loss of plasmalogens during both sepsis and SARS-CoV-2 infection. This study also indicates plasma plasmalogens should be considered in future studies as biomarkers of infection and as prognostic indicators for sepsis and COVID-19 outcomes.

Dysregulated lipids in plasma and erythrocytes of COVID-19 patients and association with mental health

“…This study also suggests that plasma plasminogen should be considered in future studies as a biomarker of infection and as a prognostic indicator of sepsis and COVID-19 outcomes 9 . Oxidative stress of translocases affects β-phosphatidylcholine triggers on erythrocyte membranes 10 .…”

Plasmalogens: Free Radical Reactivity and Identification of Trans Isomers Relevant to Biological Membranes

“…As explained in Section 1, plasmalogens present a typical vinyl ether bond, which is resistant to strong bases and reducing/oxidizing agents and is easily cleaved by acids, leading to an aldehyde function further transformed to dimethyl acetal (DMA) when the reaction is performed in methanol [23,[52][53][54]. We performed a precise evaluation of the best transesterification condition for releasing the fatty acid in the sn-2 position as the corresponding FAME.…”

“…This step is very important to treat biological samples containing plasmalogens, such as in the case of red blood cell (RBC) membranes. Indeed, the occurrence of vinyl ether hydrolysis results in the formation of a lysophospholipid derivative, affecting the behavior of the PUFA residue in sn-2 [23]. We first compared treatments of the commercially available C18 plasm 20:4-PC using alkaline conditions at room temperature (rt) using 0.5 M KOH/MeOH, and under two acidic conditions: 0.5 M (1.5%) HCl/MeOH at 100 • C and 14% BF 3 /MeOH at 50 • C, as indicated in Section 3.1.…”

“…Moreover, the vinyl ether function is susceptible to acid-catalyzed hydrolysis, forming a lysophospholipid derivative and liberating the fatty acid chain in sn-1 position as fatty aldehydes, in the form of dimethylacetal (DMA) when MeOH is present [22]. In the case of infectious diseases, such in vivo hydrolysis exerts toxicity effects, due to the reduction of membrane plasmalogens with health consequences [23]. It is worth underlining that fatty acid-DMAs are known to be formed under HCl-MeOH conditions used as the conventional protocol in the RBC membrane lipidome analyses, in order to convert the fatty acid residues of phospholipids into their corresponding fatty acid methyl esters (FAME) for GC evaluation.…”

Plasmalogens and platelet‐activating factor roles in chronic inflammatory diseases

“…It was thus proposed that a crosstalk between mitochondria and peroxisomes, which could for instance impair the beneficial physiological functions of glial cells, 95 contributes to fatigue and cognitive dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome 15 . While COVID‐19 and its long‐term association with fatigue and cognitive dysfunction was recently linked to this myalgic encephalomyelitis/chronic fatigue syndrome, notably based on their shared mechanisms involving oxidative stress, inflammation, and energy metabolic deficits observed in the two conditions, 96 plasmatic Pls levels were found to be decreased in mouse models of sepsis and SARS‐CoV‐2 infection 97 . These findings suggest that plasmatic Pls levels could serve as a biomarker of infection and a prognostic indicator for determining the lasting outcomes of immune challenges, notably induced by viral infection.…”