Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports $Pseudomonas\ aeruginosa$-driven pathology

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Bagayoko, Salimata | Leon-Icaza, Stephen Adonai | Pinilla, Miriam | Hessel, Audrey | Santoni, Karin | Péricat, David | Bordignon, Pierre-Jean | Moreau, Flavie | Eren, Elif | Boyance, Aurelien | Naser, Emmanuelle | Lefèvre, Lise | Berrone, Céline | Iakobachvili, Nino | Metais, Arnaud | Rombouts, Yoann | Lugo-Villarino, Geanncarlo | Coste, Agnès | Attrée, Ina | Frank, Dara, W. | Clevers, Hans | Peters, Peter, J. | Cougoule, Céline | Planès, Rémi | Meunier, Etienne

Edité par CCSD ; Public Library of Science -

International audience. 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.

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