Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality
Justin M. Snider, … , Maurizio Del Poeta, Floyd H. Chilton
Justin M. Snider, … , Maurizio Del Poeta, Floyd H. Chilton
Published August 24, 2021
Citation Information: J Clin Invest. 2021;131(19):e149236. https://doi.org/10.1172/JCI149236.
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Research Article Inflammation

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

Abstract

There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. 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 the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator–based (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 did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index–based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.

Authors

Justin M. Snider, Jeehyun Karen You, Xia Wang, Ashley J. Snider, Brian Hallmark, Manja M. Zec, Michael C. Seeds, Susan Sergeant, Laurel Johnstone, Qiuming Wang, Ryan Sprissler, Tara F. Carr, Karen Lutrick, Sairam Parthasarathy, Christian Bime, Hao Helen Zhang, Chiara Luberto, Richard R. Kew, Yusuf A. Hannun, Stefano Guerra, Charles E. McCall, Guang Yao, Maurizio Del Poeta, Floyd H. Chilton

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Figure 1

Untargeted lipidomics analysis and COVID-19 status.

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Untargeted lipidomics analysis and COVID-19 status. Plasma samples from ...
Plasma samples from non–COVID-19 patients, those with mild COVID-19, those with severe COVID-19, and deceased COVID-19 patients were subjected to untargeted metabolomics analyses. Lipidome data were extracted from the metabolomics data set and analyzed. (A) Volcano plots show significant alterations in the lipidome of the deceased COVID-19 patients compared with that of the non–COVID-19 patients, patients with mild COVID-19, and patients with severe COVID-19. Colored areas highlight compounds with a FC of greater than 1.5 and a FDR of less than 0.1. (B) Heatmap of the top 20 metabolites whose abundances varied markedly across non–COVID-19 patients (Non–COVID-19), patients with mild COVID-19 (Mild), patients with severe COVID-19 (Severe), and deceased COVID-19 patients (Deceased). (C) Abundances of 2 lyso-PLs, 2 FFAs, and 2 short-chain acyl carnitines extracted from the untargeted lipid data. C16:0e lyso-PC in the upper right panel is an example of a PC-containing lysolipid that did not meet the FC and FDR criteria in A and is not a primary substrate of sPLA2-IIA. The other 5 compounds were selected from the colored regions in A (FDR <0.1) and may have resulted from the action of sPLA2-IIA. The levels in each panel were further compared using a 1-sided Wilcoxon test with Holm’s correction for multiple testing. For the box plots, the upper and lower bounds indicate the 75th (Q3) and 25th (Q1) percentiles, respectively; the line within the box indicates the median value; whiskers extend to values within 1.5 IQR (IQR, Q3–Q1) of the upper or lower bound; outlying values are shown between 1.5 and 3 IQR beyond the upper or lower bound. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. (D) Model of PLA2 reaction showing how PLA2 hydrolyzes the sn-2 position of the glycerol backbone of phospholipids to form lyso-PL and FFA products.