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

Salimata Bagayoko1, Stephen Adonai Leon-Icaza1, Miriam Pinilla1

  • 1Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.

Plos Pathogens
|September 13, 2021
PubMed

Insights

Pseudomonas aeruginosa

Area of Science:

  • Microbiology
  • Cell Biology
  • Biochemistry

Background:

  • Regulated cell necrosis is crucial for immunity, but its dysregulation causes organ damage.
  • Pseudomonas aeruginosa's ExoU phospholipase induces pathological necrosis via an unclear mechanism.
  • Understanding ExoU's role in necrosis is vital for combating bacterial infections.

Purpose of the Study:

  • To elucidate the molecular and cellular mechanisms of ExoU-mediated necrosis.
  • To investigate the role of peroxidised phospholipids in ExoU activity and host cell death.
  • To explore therapeutic strategies targeting lipid peroxidation for bacterial infections.

Main Methods:

  • Investigated ExoU phospholipase activity in relation to cellular peroxidised phospholipids.
  • Assessed the impact of GPX4 (glutathione peroxidase 4) and lipid peroxidation inhibition on ExoU-dependent necrosis.
  • Evaluated bacterial elimination in vitro and in vivo models.

Main Results:

  • Cellular peroxidised phospholipids enhance ExoU phospholipase activity, driving cell necrosis.
  • GPX4 and pharmacological inhibition of lipid peroxidation significantly delay ExoU-dependent necrosis.
  • Inhibition of lipid peroxidation improves bacterial clearance in vitro and in vivo.

Conclusions:

  • ExoU utilizes peroxidised phospholipids, representing a novel virulence mechanism.
  • Targeting lipid peroxidation offers a potential therapeutic strategy against ExoU-mediated pathology.
  • This mechanism may be conserved among microbial phospholipases, including those from Burkholderia thailandensis.

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