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1. Leishmania infantum exploits the anti-ferroptosis effects of Nrf2 to escape cell death in macrophages

Author

Clément Blot, Mathilde Lavernhe, Geanncarlo Lugo-Villarino, Kimberley Coulson, Marie Salon, Margot Tertrais, Rémi Planès, Karin Santoni, Hélène Authier, Godefroy Jacquemin, Mouna Rahabi, Mélissa Parny, Isabelle Raymond Letron, Etienne Meunier, Lise Lefèvre, and Agnès Coste

Subjects
CP: Immunology, CP: Microbiology, Biology (General), QH301-705.5
Abstract

Summary: Macrophages are major host cells for the protozoan Leishmania parasite. Depending on their activation state, they either contribute to the detection and elimination of Leishmania spp. or promote parasite resilience. Here, we report that the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages plays a pivotal role in the progression of Leishmania infantum infection by controlling inflammation and redox balance of macrophages. We also highlight the involvement of the NOX2/reactive oxygen species (ROS) axis in early Nrf2 activation and, subsequently, prostaglandin E2 (PGE2)/EP2r signaling in the sustenance of Nrf2 activation upon infection. Moreover, we establish a ferroptosis-like process within macrophages as a cell death program of L. infantum and the protective effect of Nrf2 in macrophages against L. infantum death. Altogether, these results identify Nrf2 as a critical factor for the susceptibility of L. infantum infection, highlighting Nrf2 as a promising pharmacological target for the development of therapeutic approaches for the treatment of visceral leishmaniasis.

Published
2024
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2. Caspase-1-driven neutrophil pyroptosis and its role in host susceptibility to Pseudomonas aeruginosa.

Author

Karin Santoni, David Pericat, Leana Gorse, Julien Buyck, Miriam Pinilla, Laure Prouvensier, Salimata Bagayoko, Audrey Hessel, Stephen Adonai Leon-Icaza, Elisabeth Bellard, Serge Mazères, Emilie Doz-Deblauwe, Nathalie Winter, Christophe Paget, Jean-Philippe Girard, Christine T N Pham, Céline Cougoule, Renaud Poincloux, Mohamed Lamkanfi, Emma Lefrançais, Etienne Meunier, and Rémi Planès

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Multiple regulated neutrophil cell death programs contribute to host defense against infections. However, despite expressing all necessary inflammasome components, neutrophils are thought to be generally defective in Caspase-1-dependent pyroptosis. By screening different bacterial species, we found that several Pseudomonas aeruginosa (P. aeruginosa) strains trigger Caspase-1-dependent pyroptosis in human and murine neutrophils. Notably, deletion of Exotoxins U or S in P. aeruginosa enhanced neutrophil death to Caspase-1-dependent pyroptosis, suggesting that these exotoxins interfere with this pathway. Mechanistically, P. aeruginosa Flagellin activates the NLRC4 inflammasome, which supports Caspase-1-driven interleukin (IL)-1β secretion and Gasdermin D (GSDMD)-dependent neutrophil pyroptosis. Furthermore, P. aeruginosa-induced GSDMD activation triggers Calcium-dependent and Peptidyl Arginine Deaminase-4-driven histone citrullination and translocation of neutrophil DNA into the cell cytosol without inducing extracellular Neutrophil Extracellular Traps. Finally, we show that neutrophil Caspase-1 contributes to IL-1β production and susceptibility to pyroptosis-inducing P. aeruginosa strains in vivo. Overall, we demonstrate that neutrophils are not universally resistant for Caspase-1-dependent pyroptosis.

Published
2022
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3. Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology.

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, and Etienne Meunier

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
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.

Published
2021
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4. <scp>GSDMD</scp> drives canonical inflammasome‐induced neutrophil pyroptosis and is dispensable for <scp>NETosis</scp>

Author

Dhruv Chauhan, Dieter Demon, Lieselotte Vande Walle, Oonagh Paerewijck, Annalisa Zecchin, Leslie Bosseler, Karin Santoni, Rémi Planès, Silvia Ribo, Amelie Fossoul, Amanda Gonçalves, Hanne Van Gorp, Nina Van Opdenbosch, Filip Van Hauwermeiren, Etienne Meunier, Andy Wullaert, and Mohamed Lamkanfi

Subjects
Pore Forming Cytotoxic Proteins, Inflammasomes, Neutrophils, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, NADPH Oxidases, Phosphate-Binding Proteins, Pyrin, Extracellular Traps, Biochemistry, Mice, Inbred C57BL, Mice, Chemistry, NLR Family, Pyrin Domain-Containing 3 Protein, Pyroptosis, Genetics, Animals, Human medicine, Mitogens, Biology, Molecular Biology, NADP
Abstract

Neutrophils are the most prevalent immune cells in circulation, but the repertoire of canonical inflammasomes in neutrophils and their respective involvement in neutrophil IL-1 beta secretion and neutrophil cell death remain unclear. Here, we show that neutrophil-targeted expression of the disease-associated gain-of-function Nlrp3(A350V) mutant suffices for systemic autoinflammatory disease and tissue pathology in vivo. We confirm the activity of the canonical NLRP3 and NLRC4 inflammasomes in neutrophils, and further show that the NLRP1b, Pyrin and AIM2 inflammasomes also promote maturation and secretion of interleukin (IL)-1 beta in cultured bone marrow neutrophils. Notably, all tested canonical inflammasomes promote GSDMD cleavage in neutrophils, and canonical inflammasome-induced pyroptosis and secretion of mature IL-1 beta are blunted in GSDMD-knockout neutrophils. In contrast, GSDMD is dispensable for PMA-induced NETosis. We also show that Salmonella Typhimurium-induced pyroptosis is markedly increased in Nox2/Gp91(Phox)-deficient neutrophils that lack NADPH oxidase activity and are defective in PMA-induced NETosis. In conclusion, we establish the canonical inflammasome repertoire in neutrophils and identify differential roles for GSDMD and the NADPH complex in canonical inflammasome-induced neutrophil pyroptosis and mitogen-induced NETosis, respectively.

Published
2022
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5. Caspase-1-driven neutrophil pyroptosis promotes an incomplete NETosis upon Pseudomonas aeruginosa infection

Author

Serge Mazères, Stephen Adonai Leon-Icaza, Mohamed Lamkanfi, Karin Santoni, Christine T.N. Pham, Jean-Philippe Girard, Etienne Meunier, Emilie Doz-Deblauwe, Audrey Hessel, Odile Burlet-Schiltz, Christophe Paget, David Péricat, Aylward F, Yoann Rombouts, Anne Gonzalez-de-Peredo, Salimata Bagayoko, Nathalie Winter, Renaud Poincloux, Pierre-Jean Bordignon, Céline Cougoule, Rémi Planès, Emma Lefrançais, Elisabeth Bellard, Miriam Pinilla, and Abdderrahim R

Subjects
0303 health sciences, biology, Chemistry, medicine.medical_treatment, Pyroptosis, Caspase 1, Inflammasome, Inflammation, Phospholipase, 3. Good health, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Histone, Cytokine, NLRC4, medicine, biology.protein, medicine.symptom, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug
Abstract

Multiple neutrophil death programs contribute to host defense against infections. Although expressing all necessary components, neutrophils specifically fail to undergo pyroptosis, a lytic form of cell death triggered by the activation of the pro-inflammatory complex inflammasome. In the light of the arm race, we hypothesized that intrinsic neutrophil pyroptosis resistance might be bypassed in response to specific microbial species. We show that Pseudomonas aeruginosa (P. aeruginosa) stimulates Caspase-1-dependent pyroptosis in human and murine neutrophils. Mechanistically, activated NLRC4 inflammasome supports Caspase-1-driven Gasdermin-D (GSDMD) activation, IL-1β cytokine release and neutrophil pyroptosis. Furthermore, GSDMD activates Peptidyl Arginine Deaminase-4 which drives an “incomplete NETosis” where neutrophil DNA fills the cell cytosol but fails crossing plasma membrane. Finally, we show that neutrophil Caspase-1 account for IL-1β production and contributes to various P. aeruginosa strains spread in mice. Overall, we demonstrate that neutrophils are fully competent for Caspase-1-dependent pyroptosis, which drives an unsuspected “incomplete NETosis”.SummaryNeutrophils play an essential roles against infections. Although multiple neutrophil death programs contribute to host defense against infections, they fail to undergo pyroptosis, a pro-inflammatory form of cell death. Upon Infections, pyroptosis can be induced in macrophages or epithelial cells upon activation of pro-inflammatory complexes, inflammasomes that trigger Caspase-1-driven Gasdermin dependent plasma membrane lysis. In the light of host-microbe interactions, we hypothesized that yet to find microbial species might hold the capacity to overcome neutrophil resistance to inflammasome-driven pyroptosis. Among several bacterial species, we describe that the bacterium Pseudomonas aeruginosa specifically engages the NLRC4 inflammasome, which promotes Caspase-1-dependent Gasdermin-D activation and subsequent neutrophil pyroptosis. Furthermore, inflammasome-driven pyroptosis leads to DNA decondensation and expansion into the host cell cytosol but not to the so called Neutrophil Extracellular Trap (NET) release as DNA fails breaching the plasma membrane. Finally, in vivo P. aeruginosa infections highlight that Caspase-1-driven neutrophil pyroptosis is functional and is detrimental upon P. aeruginosa infection. Altogether, our results unexpectedly underline neutrophil competence for Caspase-1-dependent pyroptosis, a process that contributes to host susceptibility to P. aeruginosa infection.

Published
2021
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6. Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supportsPseudomonas aeruginosa-driven pathology

Author

Aurélien Boyance, Karin Santoni, Stephen Adonai Leon-Icaza, Hans Clevers, Yoann Rombouts, Arnaud Métais, Etienne Meunier, Agnès Coste, Emmanuelle Naser, Ina Attrée, Peter J. Peters, Rémi Planès, Audrey Hessel, Elif Eren, Salimata Bagayoko, Céline Berrone, Céline Cougoule, N. Iacobachvili, Pierre-Jean Bordignon, Miriam Pinilla, Flavie Moreau, Lise Lefèvre, and Dara W. Frank

Subjects
Pathology, medicine.medical_specialty, Necrosis, Chemistry, Pseudomonas aeruginosa, Phospholipid, Virulence, Phospholipase, GPX4, medicine.disease_cause, Lipid peroxidation, chemistry.chemical_compound, Immune system, medicine, medicine.symptom
Abstract

SummaryRegulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage.Pseudomonas aeruginosaexpresses 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 eliminationin vitroandin vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogenBurkholderia 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.

Published
2021
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7. Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports $Pseudomonas\ aeruginosa$-driven pathology

Author

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, 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, and Institute of Nanoscopy (IoN)

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
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., 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.

Published
2021
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8. Irgm2 and Gate-16 cooperatively dampen targeting of caspase-11 to Gram-negative bacterial products

Author

Pierre-Jean Bordignon, Audrey Hessel, Karima Chaoui, Rémi Planès, Jonathan C. Howard, Elif Eren, Salimata Bagayoko, Karin Santoni, Miriam Pinilla, Masahiro Yamamoto, Etienne Meunier, and Odile Burlet-Schiltz

Subjects
0303 health sciences, Host cell cytosol, Chemistry, Intracellular parasite, medicine.medical_treatment, Pyroptosis, Inflammasome, Caspase-11, Cell biology, 03 medical and health sciences, Classical complement pathway, 0302 clinical medicine, Immune system, Cytokine, medicine, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug
Abstract

Inflammatory caspase-11 (rodent) and caspases-4 and -5 (human) detect gram-negative bacterial component LPS in the host cell cytosol, which promotes activation of the non-canonical inflammasome. Although non-canonical inflammasome-induced pyroptosis and IL-1 related cytokine release is of importance to mount an efficient immune response against various bacteria, its unrestrained activation drives sepsis. This suggests that cellular components might tightly control the threshold level of the non-canonical inflammasome in order to ensure efficient but not deleterious inflammatory response. Here we show that the IFN-inducible protein Irgm2 and the ATG8 family member Gate-16 cooperatively slow down non-canonical inflammasome activation both in macrophages and in vivo. Specifically, the Irgm2/Gate-16 axis dampens caspase-11 targeting to intracellular bacteria, which lower caspase-11-mediated pyroptosis and cytokine release. Specifically, deficiency in Irgm2 or Gate16 opens an alternative road for caspase-11 targeting to intracellular bacteria, independently of the classical pathway driven by the Guanylate Binding Proteins (GBPs). Thus, our findings provide new molecular effectors involved at fine-tuning the optimal non-canonical inflammasome response and add novel insights in the understanding of the immune pathways they control.

Published
2020
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9. Irgm2 and Gate‐16 cooperatively dampen Gram‐negative bacteria‐induced caspase‐11 response

Author

Thomas Henry, Rémi Planès, Karima Chaoui, Karin Santoni, Jonathan C. Howard, Odile Burlet-Schiltz, Masahiro Yamamoto, Elif Eren, Audrey Hessel, Salimata Bagayoko, Brice Lagrange, Etienne Meunier, Miriam Pinilla, Pierre-Jean Bordignon, 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), Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation (I2BA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-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, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Gram-negative bacteria, infections/Interferons, medicine.medical_treatment, Immunology, Caspase-11, Biochemistry, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Irgm2, Genetics, medicine, Molecular Biology, Gate-16, 030304 developmental biology, 0303 health sciences, Host cell cytosol, biology, Chemistry, Intracellular parasite, [SDV.BA]Life Sciences [q-bio]/Animal biology, Pyroptosis, Inflammasome, Articles, biology.organism_classification, non-canonical inflammasome Subject Categories Autophagy & Cell Death, Cell biology, Virology & Host Pathogen Interaction, Cytokine, 030217 neurology & neurosurgery, medicine.drug
Abstract

Inflammatory caspase-11 (rodent) and caspases-4/5 (humans) detect the Gram-negative bacterial component LPS within the host cell cytosol, promoting activation of the non-canonical inflammasome. Although non-canonical inflammasome-induced pyroptosis and IL-1-related cytokine release are crucial to mount an efficient immune response against various bacteria, their unrestrained activation drives sepsis. This suggests that cellular components tightly control the threshold level of the non-canonical inflammasome in order to ensure efficient but non-deleterious inflammatory responses. Here, we show that the IFN-inducible protein Irgm2 and the ATG8 family member Gate-16 cooperatively counteract Gram-negative bacteria-induced non-canonical inflammasome activation, both in cultured macrophages and in vivo. Specifically, the Irgm2/Gate-16 axis dampens caspase-11 targeting to intracellular bacteria, which lowers caspase-11-mediated pyroptosis and cytokine release. Deficiency in Irgm2 or Gate16 induces both guanylate binding protein (GBP)-dependent and GBP-independent routes for caspase-11 targeting to intracellular bacteria. Our findings identify molecular effectors that fine-tune bacteria-activated non-canonical inflammasome responses and shed light on the understanding of the immune pathways they control. info:eu-repo/semantics/publishedVersion

Published
2020
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10. Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells

Author

Rémi Planès, Miriam Pinilla, Karin Santoni, Audrey Hessel, Charlotte Passemar, Kenneth Lay, Perrine Paillette, Ana-Luiza Chaves Valadão, Kim Samirah Robinson, Paul Bastard, Nathaniel Lam, Ricardo Fadrique, Ida Rossi, David Pericat, Salimata Bagayoko, Stephen Adonai Leon-Icaza, Yoann Rombouts, Eric Perouzel, Michèle Tiraby, Qian Zhang, Pietro Cicuta, Emmanuelle Jouanguy, Olivier Neyrolles, Clare E. Bryant, Andres R. Floto, Caroline Goujon, Franklin Zhong Lei, Guillaume Martin-Blondel, Stein Silva, Jean-Laurent Casanova, Céline Cougoule, Bruno Reversade, Julien Marcoux, Emmanuel Ravet, Etienne Meunier, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), InvivoGen Europe, Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Molecular Immunity Unit [Cambridge, UK] (Department of Medicine), University of Cambridge [UK] (CAM), Institute of Medical Biology [Singapore Singapore], Genome Institute of Singapore (GIS), Agency for science, technology and research [Singapore] (A*STAR), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Department of Veterinary Medicine, University of Cambridge, Cambridge, UK, School of Clinical Medicine, Cavendish Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], Skin Research Institute of Singapore [Singapore, Singapore] (SRIS / A*STAR), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de réanimation infantile [CHU Purpan], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), Institute of Molecular and Cell Biology, National University of Singapore (NUS)-Agency for science, technology and research [Singapore] (A*STAR), Yong Loo Lin School of Medicine [Singapore], Koç University, This project was funded by grants from the Fondation pour la Recherche Médicale (F.R.M.) and the ERC StG (INFLAME) to E.M., the ERC StG (ANTIViR) to C.G., and the French Ministry of Health with the participation of the Groupement Interrégional de Recherche Clinique et d’Innovation Sud-Ouest Outre-Mer (PHRCI 2020 IMMUNOMARK-COV) to G.-M.B. The ASB3 structure is supported by LABEX, Investissement d’Avenir and foundation Bettencourt grants to O.N. M.P. and R.P. were, respectively, funded by a CIFRE PhD fellowship and a research grant from InvivoGen. S.B. is supported by a PhD fellowship from Mali Ministry of Education and from the FRM (FDT 12794)., ANR-12-BSV3-0002,B-TB,Rôle des lymphocytes B dans l'immunité et l'inflammation tuberculeuse(2012), ANR-18-CE44-0005,DCIR-TB,Etude des mécanismes impliqués dans la modulation de la signalisation par les interférons de type I et l'immunité anti-tuberculeuse par la lectine de type C DCIR(2018), Cougoule, Céline, BLANC - Rôle des lymphocytes B dans l'immunité et l'inflammation tuberculeuse - - B-TB2012 - ANR-12-BSV3-0002 - BLANC - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Etude des mécanismes impliqués dans la modulation de la signalisation par les interférons de type I et l'immunité anti-tuberculeuse par la lectine de type C DCIR - - DCIR-TB2018 - ANR-18-CE44-0005 - AAPG2018 - VALID, Center for Reproductive Medicine, ACS - Heart failure & arrhythmias, Amsterdam Reproduction & Development, Reversade, Bruno, Planes, R., Pinilla, M., Santoni, K., Hessel, A., Passemar, C., Lay, K., Paillette, P., Valadao, A.C., Robinson, K.S., Bastard, P., Lam, N., Fadrique, R., Rossi, I., Pericat, D., Bagayoko, S., Leon-Icaza, S.A., Rombouts, Y., Perouzel, E., Tiraby, M., COVID Human Genetic Effort, Zhang, Q., Cicuta, P., Jouanguy, E., Neyrolles, O., Bryant, C.E., Floto, A.R., Goujon, C., Lei, F.Z., Martin-Blondel, G., Silva, S., Casanova, J.L., Cougoule, C., Marcoux, J., Ravet, E., Meunier, E., and School of Medicine

Subjects
Pore Forming Cytotoxic Proteins, Caspase 3, Inflammasomes, SARS-CoV-2, [SDV]Life Sciences [q-bio], pyroptosis, COVID-19, NLR Proteins, Cell Biology, 3CL proteases, Epithelial cells, Gasdermins, NLRP1 inflammasome, Pyroptosis, Phosphate-Binding Proteins, epithelial cells, [SDV] Life Sciences [q-bio], Humans, Biochemistry and molecular biology, Cell biology, Lung, Molecular Biology, Coronavirus 3C Proteases, Peptide Hydrolases
Abstract

Inflammation observed in SARS-CoV-2-infected patients suggests that inflammasomes, proinflammatory intracellular complexes, regulate various steps of infection. Lung epithelial cells express inflammasome-forming sensors and constitute the primary entry door of SARS-CoV-2. Here, we describe that the NLRP1 in-flammasome detects SARS-CoV-2 infection in human lung epithelial cells. Specifically, human NLRP1 is cleaved at the Q333 site by multiple coronavirus 3CL proteases, which triggers inflammasome assembly and cell death and limits the production of infectious viral particles. Analysis of NLRP1-associated pathways unveils that 3CL proteases also inactivate the pyroptosis executioner Gasdermin D (GSDMD). Subsequently, caspase-3 and GSDME promote alternative cell pyroptosis. Finally, analysis of pyroptosis markers in plasma from COVID-19 patients with characterized severe pneumonia due to autoantibodies against, or inborn errors of, type I interferons (IFNs) highlights GSDME/caspase-3 as potential markers of disease severity. Overall, our findings identify NLRP1 as a sensor of SARS-CoV-2 infection in lung epithelia., Fondation pour la Recherche Med-icale (F.R.M.); European Union (EU); Horizon 2020; ERC StG (INFLAME); ERC StG (ANTIViR); French Ministry of Health; Goupe-ment Interregional de Recherche Clinique et d’Innovation Sud-Ouest Outre-Mer (PHRCI 2020 IMMUNOMARK-COV); LABEX; CIFRE PhD Fellowship; Investissement d'Avenir and foundation Bettencourt; InvivoGen; Mali Ministry of Education; Vaincre La Mucoviscidose (VLM); InvivoGen

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