Medical College of Wisconsin
CTSIResearch InformaticsREDCap

Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. PLoS Pathog 2021 Sep;17(9):e1009927

Date

09/14/2021

Pubmed ID

34516571

Pubmed Central ID

PMC8460005

DOI

10.1371/journal.ppat.1009927

Scopus ID

2-s2.0-85115220583 (requires institutional sign-in at Scopus site)   22 Citations

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.

Author List

Bagayoko S, Leon-Icaza SA, Pinilla M, Hessel A, Santoni K, Péricat D, Bordignon PJ, 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

Author

Dara W. Frank PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

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