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 Frank; Hans Clevers; Peter J Peters; Céline Cougoule; Rémi Planès; Etienne Meunier

doi:10.1371/journal.ppat.1009927

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

13 Citations (Scopus)

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 language	English
Pages (from-to)	e1009927
Journal	PLoS Pathogens
Volume	17
Issue number	9
DOIs	https://doi.org/10.1371/journal.ppat.1009927
Publication status	Published - Sept 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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10.1371/journal.ppat.1009927

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Bagayoko, S., Leon-Icaza, S. A., Pinilla, M., Hessel, A., Santoni, K., Péricat, D., Bordignon, P.-J., Moreau, F., Eren, E., Boyancé, A., Naser, E., Lefèvre, L., Berrone, C., Iakobachvili, N., Metais, A., Rombouts, Y., Lugo-Villarino, G., Coste, A., Attrée, I., ... Meunier, E. (2021). Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. PLoS Pathogens, 17(9), e1009927. https://doi.org/10.1371/journal.ppat.1009927

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title = "Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology",

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.",

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year = "2021",

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Bagayoko, S, Leon-Icaza, SA, Pinilla, M, Hessel, A, Santoni, K, Péricat, D, Bordignon, P-J, Moreau, F, Eren, E, Boyancé, A, Naser, E, Lefèvre, L, Berrone, C, Iakobachvili, N, Metais, A, Rombouts, Y, Lugo-Villarino, G, Coste, A, Attrée, I, Frank, DW, Clevers, H, Peters, PJ, Cougoule, C, Planès, R & Meunier, E 2021, 'Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology', PLoS Pathogens, vol. 17, no. 9, pp. e1009927. https://doi.org/10.1371/journal.ppat.1009927

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

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.

KW - Animals

KW - Bacterial Proteins/metabolism

KW - Host-Pathogen Interactions/physiology

KW - Humans

KW - Lipid Peroxidation/physiology

KW - Mice

KW - Mice, Knockout

KW - Necrosis/metabolism

KW - Pseudomonas Infections/metabolism

KW - Pseudomonas aeruginosa/metabolism

KW - Virulence/physiology

U2 - 10.1371/journal.ppat.1009927

DO - 10.1371/journal.ppat.1009927

M3 - Article

C2 - 34516571

SN - 1553-7366

VL - 17

SP - e1009927

JO - PLoS Pathogens

JF - PLoS Pathogens

IS - 9

ER -

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

Abstract

Keywords

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