1. Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology.
- Author
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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, and Meunier E
- Subjects
- Animals, Humans, Mice, Mice, Knockout, Necrosis metabolism, Pseudomonas Infections pathology, Pseudomonas aeruginosa metabolism, Virulence physiology, Bacterial Proteins metabolism, Host-Pathogen Interactions physiology, Lipid Peroxidation physiology, Pseudomonas Infections metabolism, Pseudomonas aeruginosa pathogenicity
- 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., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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