Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports $Pseudomonas\ aeruginosa$-driven pathology
| Autor: | Flavie Moreau, Geanncarlo Lugo-Villarino, Aurélien Boyance, Arnaud Métais, Peter J. Peters, Karin Santoni, Céline Cougoule, Stephen Adonai Leon-Icaza, Hans Clevers, Lise Lefèvre, Etienne Meunier, Yoann Rombouts, Agnès Coste, Pierre-Jean Bordignon, Miriam Pinilla, Emmanuelle Naser, Audrey Hessel, David Péricat, Ina Attrée, Rémi Planès, Nino Iakobachvili, Dara W. Frank, Elif Eren, Salimata Bagayoko, Céline Berrone |
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| Přispěvatelé: | Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Maastricht University [Maastricht], Groupe Pathogenèse Bactérienne et Réponses Cellulaires / Bacterial Pathogenesis and Cellular Responses Group (IBS-PBRC), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Medical College of Wisconsin [Milwaukee] (MCW), Hubrecht Institute [Utrecht, Netherlands], University Medical Center [Utrecht]-Royal Netherlands Academy of Arts and Sciences (KNAW), ANR-18-CE14-0007,ENDIABAC,LE SYSTEME NERVEUX ENTERIQUE COMME CIBLE POUR TRAITER LE DIABETE DE TYPE 2 : ROLES DES LIPIDES BIOACTIFS BACTERIENS(2018), ANR-17-CE11-0006,MacGlycoTB,Rôle de ST8SIA4 et de la polysialylation des protéines des macrophages dans la réponse immunitaire contre une infection par Mycobacterium tuberculosis(2017), European Project: 804249,INFLAME, Hubrecht Institute for Developmental Biology and Stem Cell Research, ATTREE, Ina, APPEL À PROJETS GÉNÉRIQUE 2018 - LE SYSTEME NERVEUX ENTERIQUE COMME CIBLE POUR TRAITER LE DIABETE DE TYPE 2 : ROLES DES LIPIDES BIOACTIFS BACTERIENS - - ENDIABAC2018 - ANR-18-CE14-0007 - AAPG2018 - VALID, Rôle de ST8SIA4 et de la polysialylation des protéines des macrophages dans la réponse immunitaire contre une infection par Mycobacterium tuberculosis - - MacGlycoTB2017 - ANR-17-CE11-0006 - AAPG2017 - VALID, Deciphering the host and microbial grounds that license inflammasome-mediated execution - INFLAME - 804249 - INCOMING, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, RS: M4I - Nanoscopy, Institute of Nanoscopy (IoN) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | 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 |
| ISSN: | 1553-7366 1553-7374 |
| DOI: | 10.1371/journal.ppat.1009927⟩ |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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