Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology
Salimata Bagayoko, Stephen Adonai Leon‐Icaza, Miriam Pinilla, Audrey Hessel, Karin Santoni, David Péricat, Pierre‐Jean Bordignon, Flavie Moreau, Elif Eren, Aurélien Boyance, Emmanuelle Näser, Lise Lefèvre, Céline Berrone, Nino Iakobachvili, Arnaud Métais, Yoann Rombouts, Geanncarlo Lugo‐Villarino, Agnès Coste, Ina Attrée, Dara W. Frank, Hans Clevers, Peter J. Peters, Céline Cougoule, Rémi Planès, Étienne Meunier
Abstract
Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.