Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology.
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....
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Public Library of Science (PLoS)
2021
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oai:doaj.org-article:ac74c14209964749a163336c8cf869b02021-12-02T20:00:11ZHost phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology.1553-73661553-737410.1371/journal.ppat.1009927https://doaj.org/article/ac74c14209964749a163336c8cf869b02021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009927https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Regulated 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.Salimata BagayokoStephen Adonai Leon-IcazaMiriam PinillaAudrey HesselKarin SantoniDavid PéricatPierre-Jean BordignonFlavie MoreauElif ErenAurélien BoyancéEmmanuelle NaserLise LefèvreCéline BerroneNino IakobachviliArnaud MetaisYoann RomboutsGeanncarlo Lugo-VillarinoAgnès CosteIna AttréeDara W FrankHans CleversPeter J PetersCéline CougouleRémi PlanèsEtienne MeunierPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009927 (2021) |
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DOAJ |
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DOAJ |
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EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 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 Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Salimata Bagayoko |
| title |
Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. |
| title_short |
Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. |
| title_full |
Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. |
| title_fullStr |
Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. |
| title_full_unstemmed |
Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology. |
| title_sort |
host phospholipid peroxidation fuels exou-dependent cell necrosis and supports pseudomonas aeruginosa-driven pathology. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/ac74c14209964749a163336c8cf869b0 |
| work_keys_str_mv |
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