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 Boyancé, Emmanuelle Naser, Lise Lefèvre, Céline Berrone, Nino Iakobachvili, Arnaud Metais, Yoann Rombouts, Geanncarlo Lugo-Villarino, Agnès Coste, Ina Attrée, Dara W FrankHans Clevers, Peter J Peters, Céline Cougoule, Rémi Planès, Etienne Meunier

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)e1009927
JournalPLoS Pathogens
Volume17
Issue number9
DOIs
Publication statusPublished - Sep 2021

Keywords

  • Animals
  • Bacterial Proteins/metabolism
  • Host-Pathogen Interactions/physiology
  • Humans
  • Lipid Peroxidation/physiology
  • Mice
  • Mice, Knockout
  • Necrosis/metabolism
  • Pseudomonas Infections/metabolism
  • Pseudomonas aeruginosa/metabolism
  • Virulence/physiology

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