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 2

Association between sPLA2-IIA and COVID-19 status.

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Association between sPLA2-IIA and COVID-19 status. (A) sPLA2-IIA levels ...
(A) sPLA2-IIA levels were determined in 127 plasma samples and are shown here sorted within each group. The inset box plot compares the log-transformed data across groups and shows the medians and quartiles. Groups were compared using a 1-sided Wilcoxon test with Holm’s correction for multiple testing. ***P < 0.001 and ****P < 0.0001. Pairwise comparisons were computed from a linear model that included age and sex, and P values were adjusted for multiple comparisons. (B) sPLA2 enzymatic activity within plasma was assayed in a selected subset of samples. In the box plots in A and B, the upper and lower bounds designate 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. (C) Scatter plot shows plasma sPLA2-IIA levels versus sPLA2 activity in the selected subset of samples. Enzyme levels and activity were strongly correlated, indicating that plasma levels of sPLA2-IIA reflect the levels of active enzyme in the larger sample set. (D) A heatmap showing the significant Spearman correlations (FDR <0.05) between sPLA2-IIA and other clinical indices of disease severity. Indices that were positively or negatively correlated with sPLA2-IIA are as indicated. Indices with missing values above 25 were removed, and those with a skewness (absolute value) below 1.0 were log transformed. Index values were mean centered and scaled according to the SD. Blue to red represents low to high index values, with color intensity indicating the value magnitude (see the color scheme). Missing values are shown in gray.