Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology

Bagayoko, S.; Leon-Icaza, S.-A.; Pinilla, M.; Hessel, A.; Santoni, K.; Bordignon, P.-J.; Moreau, F.; Eren, E.; Boyance, A.; Naser, E.; Lefevre, L.; Berrone, C.; Iacobachvili, N.; Metais, A.; Rombouts, Y.; Coste, A.; Attree, I.; Frank, D. W.; Clevers, H.; Peters, P. J.; Cougoule, C.; Planes, R.; Meunier, E.

doi:10.1101/2021.02.17.431580

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bioRxiv · 10.1101/2021.02.17.431580

Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology

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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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Bagayoko, S., Leon-Icaza, S.-A., Pinilla, M., Hessel, A., Santoni, K., Bordignon, P.-J., Moreau, F., Eren, E., Boyance, A., Naser, E., Lefevre, L., Berrone, C., Iacobachvili, N., Metais, A., Rombouts, Y., Coste, A., Attree, I., Frank, D. W., Clevers, H., Peters, P. J., Cougoule, C., Planes, R., Meunier, E.. 2021-02-17. Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. https://doi.org/10.1101/2021.02.17.431580

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