Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality

Abstract

There is an urgent need to identify cellular/molecular mechanisms responsible for severe COVID-19 progressing to mortality. We initially performed untargeted/targeted lipidomics and focused biochemistry on 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in severe COVID-19 patients.Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 Group IIA (sPLA2-IIA), with a median value 9.6-fold higher than mild patients and 5.0-fold higher than severe COVID-19 survivors. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in stratifying patients that succumbed to COVID-19. Random forest analysis and LASSO-based regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than either alone. An independent cohort (n=154) confirmed higher plasma sPLA2-IIA levels in deceased patients vs. severe or mild COVID-19, with the PLA-BUN indexbased decision tree satisfactorily stratifying mild, severe, and deceased COVID-19 patients. With clinically tested inhibitors available, this study supports sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.

Surfactant Protein-A Function: Knowledge Gained From SP-A Knockout Mice

“…SP-A, via its ability to inhibit surfactant phospholipid hydrolysis and thus maintain, to a certain extent a well-functioning surfactant, plays a protective role in lung injury. This is of great relevance to the current Covid-19 pandemic, as sPLA2-IIA was shown to associate with markers more likely to lead to mortality after SARS-CoV-2 infection (63).…”

Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

“…Recent data has highlighted a new link between hGIIA and SARS-CoV-2 infection during the COVID-19 pandemic [ 97 ]. Out of 80 clinical indices measured, including age and body mass index, hGIIA and blood urea nitrogen (BUN) were the strongest predictors of severe disease, with a decision tree based on these two indicators being able to stratify patients with mild severe or fatal infection on a validation cohort of COVID-positive patients.…”

“…Out of 80 clinical indices measured, including age and body mass index, hGIIA and blood urea nitrogen (BUN) were the strongest predictors of severe disease, with a decision tree based on these two indicators being able to stratify patients with mild severe or fatal infection on a validation cohort of COVID-positive patients. Sars-CoV-2 infection also alters the lipidome, resulting in higher concentrations of lyso-PE and lyso-PS, with no changes in lyso-PC, which is a hallmark of hGIIA activity [ 97 ]. Other research suggests COVID-19 may also increase levels of PS on the surface of the cell membrane, exposing cells to catalytic activity of hGIIA [ 97 , 98 ].…”

“…Sars-CoV-2 infection also alters the lipidome, resulting in higher concentrations of lyso-PE and lyso-PS, with no changes in lyso-PC, which is a hallmark of hGIIA activity [ 97 ]. Other research suggests COVID-19 may also increase levels of PS on the surface of the cell membrane, exposing cells to catalytic activity of hGIIA [ 97 , 98 ]. The authors suggest that hGIIA may mediate severe COVID-19 disease and as its expression is closely linked to disease outcome, that hGIIA is an attractive therapeutic target.…”

The interaction of secreted phospholipase A2-IIA with the microbiota alters its lipidome and promotes inflammation

“…Under infectious and inflammatory conditions, sPLA 2 -IIA expression is highly induced in numerous cell types, including endothelial, hepatic, renal, smooth muscle, macrophages, mast cells, platelets, astrocytes, and glial cells (34,45,(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). The serum concentration of sPLA 2 -IIA can increase up to 1000fold during sepsis, to reach concentrations of ~5 μg/mL (~350 nM) (64), and recent studies revealed that it is also induced in COVID-19 patients (65). Investigation of the gene promoter revealed that sPLA 2 -IIA is induced by proinflammatory cytokines such as IL-1β, IL-6, and TNF-α (66-69), while activation of TLR and nucleotide-binding oligomerization domain-like receptors (NLR) by pathogen-associated molecular patterns (PAMPs) also trigger sPLA 2 -IIA expression through the NF-κB pathway (70)(71)(72)(73)(74).…”