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Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports $Pseudomonas\ aeruginosa$-driven pathology
- Source :
- PLoS Pathogens, PLoS Pathogens, 2021, 17 (9), pp.e1009927. ⟨10.1371/journal.ppat.1009927⟩, PLOS Pathogens, PLoS Pathogens, 17(9). Public Library of Science, PLoS Pathogens, Vol 17, Iss 9, p e1009927 (2021), PLoS Pathogens, Public Library of Science, 2021, 17 (9), pp.e1009927. ⟨10.1371/journal.ppat.1009927⟩, PLOS PATHOGENS, 17(9):e1009927. Public Library of Science
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
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.<br />Author summary Although a proper activation of various regulated cell necrosis confer a significant advantage against various infectious agents, their dysregulation drives host tissue damages that can end up with fatal sepsis. Specifically, 30% of the bacterial strains of Pseudomonas aeruginosa (P. aeruginosa) express the phospholipase A2-like toxin ExoU that is injected into host target cells through the Type-3 Secretion System. This toxin induces, through a yet unknown mechanism, a strong and fast necrotic cell death that supports fatal respiratory infections. Therefore, in this study, we sought to determine the cellular mechanisms by which ExoU triggers host cell necrosis. In this context, we found that ExoU exploits basal cellular phospholipid peroxidation to promote cell necrosis. Mechanistically, host cell lipid peroxidation stimulates ExoU phospholipase activity, which then triggers a pathological cell necrosis both in vitro and in vivo. Altogether, our results unveil that targeting host cell lipid peroxidation constitutes a virulence mechanism developed by microbial phospholipases, a process that contributes to P. aeruginosa-mediated pathology.
- Subjects :
- Pathology
Hydrolases
Necrosis/metabolism
GPX4
Pathology and Laboratory Medicine
Biochemistry
Lipid peroxidation
Mice
0302 clinical medicine
Animal Cells
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Biology (General)
0303 health sciences
Bacterial Proteins/metabolism
Esterases
Lipids
3. Good health
Bacterial Pathogens
Pseudomonas aeruginosa/metabolism
Organoids
Medical Microbiology
Biological Cultures
Cellular Types
medicine.medical_specialty
QH301-705.5
Virulence/physiology
Knockout
Immune Cells
Immunology
Virulence
PATATIN-LIKE PHOSPHOLIPASES
Transfection
Microbiology
03 medical and health sciences
IMMUNE RECOGNITION
Necrosis
Signs and Symptoms
Bacterial Proteins
Pseudomonas
Genetics
A(2) ENZYMES
Humans
Pseudomonas Infections
CYTOTOXIN EXOU
Molecular Biology Techniques
Microbial Pathogens
Molecular Biology
Lipid Peroxidation/physiology
Blood Cells
Bacteria
Macrophages
Organisms
Biology and Life Sciences
Proteins
[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Parasitology
Lipid Peroxidation
Immunologic diseases. Allergy
Clinical Medicine
030217 neurology & neurosurgery
Phospholipase
medicine.disease_cause
chemistry.chemical_compound
White Blood Cells
Medicine and Health Sciences
OXIDATIVE STRESS
Organ Cultures
Phospholipids
Mice, Knockout
Chemistry
DEATH
Pseudomonas Aeruginosa
LIPID-PEROXIDATION
Enzymes
Host-Pathogen Interactions/physiology
Phospholipases
SECRETION SYSTEM
Host-Pathogen Interactions
[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
medicine.symptom
Pathogens
Research Article
Phospholipid
Research and Analysis Methods
Immune system
Virology
medicine
Animals
030304 developmental biology
Pseudomonas aeruginosa
Pseudomonas Infections/metabolism
Cell Biology
RC581-607
FERROPTOSIS
Enzymology
[SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Subjects
Details
- Language :
- English
- ISSN :
- 15537366 and 15537374
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens, PLoS Pathogens, 2021, 17 (9), pp.e1009927. ⟨10.1371/journal.ppat.1009927⟩, PLOS Pathogens, PLoS Pathogens, 17(9). Public Library of Science, PLoS Pathogens, Vol 17, Iss 9, p e1009927 (2021), PLoS Pathogens, Public Library of Science, 2021, 17 (9), pp.e1009927. ⟨10.1371/journal.ppat.1009927⟩, PLOS PATHOGENS, 17(9):e1009927. Public Library of Science
- Accession number :
- edsair.doi.dedup.....5e894e6c2b90a46e338f26354fa5a061