Group IIA Secreted Phospholipase A2 Plays a Central Role in the Pathobiology of COVID-19

Snider, J. M.; You, J. K.; Wang, X.; Snider, A. J.; Hallmark, B.; Seeds, M. C.; Sergeant, S.; Johnstone, L.; Wang, Q.; Sprissler, R.; Zhang, H. H.; Luberto, C.; Kew, R. R.; Hannun, Y. A.; McCall, C. E.; Yao, G.; Del Poeta, M.; Chilton, F. H.

There is an urgent need to identify cellular and molecular mechanisms responsible for severe COVID-19 disease accompanied by multiple organ failure and high mortality rates. Here, we performed untargeted/targeted lipidomics and focused biochemistry on 127 patient plasma samples, and showed high levels of circulating, enzymatically active secreted phospholipase A2 Group IIA (sPLA2-IIA) in severe and fatal COVID-19 disease compared with uninfected patients or mild illness. Machine learning demonstrated that sPLA2-IIA effectively stratifies severe from fatal COVID-19 disease. We further introduce a PLA-BUN index that combines sPLA2-IIA and blood urea nitrogen (BUN) threshold levels as a critical risk factor for mitochondrial dysfunction, sustained inflammatory injury and lethal COVID-19. With the availability of clinically tested inhibitors of sPLA2-IIA, our study opens the door to a precision intervention using indices discovered here to reduce COVID-19 mortality.