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.

Tara Ann Burns, Marimuthu Subathra, Paola Signorelli, Young Choi, Xiaofeng Yang, Yong Wang, Maristella Villani, Kapil Bhalla, Daohong Zhou, Chiara Luberto

Fungal infections pose a significant risk for the increasing population of individuals who are immunocompromised. Phagocytes play an important role in immune defense against fungal pathogens, but the interactions between host and fungi are still not well understood. Sphingolipids have been shown to play an important role in many cell functions, including the function of phagocytes. In this review, we discuss major findings that relate to the importance of sphingolipids in macrophage and neutrophil function and the role of macrophages and neutrophils in the most common types of fungal infections, as well as studies that have linked these three concepts to show the importance of sphingolipid signaling in immune response to fungal infections.

Justin M. Snider, Magali Trayssac, Christopher J. Clarke, Nicholas Schwartz, Ashley J. Snider, Lina M. Obeid, Chiara Luberto, Yusuf A. Hannun

Justin M. Snider, Ashley J. Snider, Lina M. Obeid, Chiara Luberto, Yusuf A. Hannun