TY - JOUR
T1 - Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology
AU - Bagayoko, Salimata
AU - Leon-Icaza, Stephen Adonai
AU - Pinilla, Miriam
AU - Hessel, Audrey
AU - Santoni, Karin
AU - Péricat, David
AU - Bordignon, Pierre Jean
AU - Moreau, Flavie
AU - Eren, Elif
AU - Boyancé, Aurélien
AU - Naser, Emmanuelle
AU - Lefèvre, Lise
AU - Berrone, Céline
AU - Iakobachvili, Nino
AU - Metais, Arnaud
AU - Rombouts, Yoann
AU - Lugo-Villarino, Geanncarlo
AU - Coste, Agnès
AU - Attrée, Ina
AU - Frank, Dara W.
AU - Clevers, Hans
AU - Peters, Peter J.
AU - Cougoule, Céline
AU - Planès, Rémi
AU - Meunier, Etienne
N1 - Publisher Copyright:
Copyright: © 2021 Bagayoko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85115220583
U2 - 10.1371/journal.ppat.1009927
DO - 10.1371/journal.ppat.1009927
M3 - Article
C2 - 34516571
AN - SCOPUS:85115220583
SN - 1553-7366
VL - 17
SP - 1
EP - 29
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 9
M1 - e1009927
ER -