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

PLoS Pathog. 2021 Sep 13;17(9):e1009927. doi: 10.1371/journal.ppat.1009927. eCollection 2021 Sep.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / metabolism*
  • Host-Pathogen Interactions / physiology*
  • Humans
  • Lipid Peroxidation / physiology*
  • Mice
  • Mice, Knockout
  • Necrosis / metabolism
  • Pseudomonas Infections / metabolism*
  • Pseudomonas Infections / pathology
  • Pseudomonas aeruginosa / metabolism
  • Pseudomonas aeruginosa / pathogenicity*
  • Virulence / physiology

Substances

  • Bacterial Proteins
  • pseudomonas exoprotein A protein, Pseudomonas aeruginosa

Grant support

This project was funded by grants from the National Research Agency (ANR, Endiabac), FRM “Amorçage Jeunes Equipes” (AJE20151034460), ERC StG (INFLAME 804249) and ATIP-Avenir program to EM, from National Research Agency (ANR, MacGlycoTB) to YR, from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID, 2020) to RP, from the Van Gogh Programme to IPBS-M4i institutes, from Invivogen-CIFRE collaborative PhD fellowship to MP and from the FRM (FDT202106012794), Mali and Campus France cooperative agencies to SB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.