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3. The pig as a model to determine the origins of cystic fibrosis lung disease

Author

Caballero, Ignacio, Guillon, Antoine, barc, Celine, Lantier, Isabelle, Berri, Mustapha, Chevaleyre, Claire, Olivier, Michel, Melo, Sandrine, Brea, Deborah, Bähr, Andrea, Wolf, E., Klymiuk, Nikolai, Si-Tahar, Mustapha, ProdInra, Migration, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme d'Infectiologie Expérimentale (PFIE), Institut National de la Recherche Agronomique (INRA), Gene Center and Center for Innovative Medical Models (CIMM), and Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT)

Subjects
[SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.BA]Life Sciences [q-bio]/Animal biology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2015

4. The pig as a model for the study of the early immune response to Pseudomonas Aeruginosa

Author

Berri, Mustapha, Riou, Mickaël, barc, Celine, Brea, Deborah, Chevaleyre, Claire, Pezant, Jérémy, Melo, Sandrina, Delaunay, Rémi, Olivier, Michel, Guillon, Antoine, Ramphal, R., Sarradin, Pierre, Buzoni, Dominique, Si-Tahar, Mustapha, Meurens, Francois, Attuci, Sylvie, Caballero, Ignacio, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Plateforme d'Infectiologie Expérimentale (PFIE), Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU de Tours), ProdInra, Migration, and Institut National de la Recherche Agronomique (INRA)-Université de Tours

Subjects
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2014

5. Pseudomonas aeruginosa proteolytically alters the interleukin 22-dependent lung mucosal defense

Author

Guillon, Antoine, primary, Brea, Deborah, additional, Morello, Eric, additional, Tang, Aihua, additional, Jouan, Youenn, additional, Ramphal, Reuben, additional, Korkmaz, Brice, additional, Perez-Cruz, Magdiel, additional, Trottein, Francois, additional, O'Callaghan, Richard J., additional, Gosset, Philippe, additional, and Si-Tahar, Mustapha, additional

Published
2016
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6. Neutrophils can disarm NK cell response through cleavage of NKp46

Author

Valayer, Alexandre, primary, Brea, Deborah, additional, Lajoie, Laurie, additional, Avezard, Leslie, additional, Combes-Soia, Lucie, additional, Labas, Valerie, additional, Korkmaz, Brice, additional, Thibault, Gilles, additional, Baranek, Thomas, additional, and Si-Tahar, Mustapha, additional

Published
2016
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7. Maintenance and phenotyping of a pig model for the study of early pathogenesis of cystic fibrosis

Author

Guillon, Antoine, Barc, Celine, Berri, El Mostafa, Chevaleyre, Claire, Olivier, Michel, Melo, Sandrina, Brea, Deborah, Riou, Mickaël, Pezant, Jérémy, Cognié, Juliette, Adriaensen, Hans, Lecompte, François, Villemagne, T., Winter, Nathalie, Bähr, A., Wolf, E., Klymiuk, Nikolai, Attuci, Sylvie, Ramphal, R., Sarradin, Pierre, Buzoni-Gatel, Dominique, Si-Tahar, Mustapha, and Caballero, Ignacio

Subjects
modèle animal, gène cftr, Médecine humaine et pathologie, Human health and pathology, scintigraphie, mucoviscidose, porc
Published
2014

8. Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

Author

Guillon, Antoine, primary, Jouan, Youenn, additional, Brea, Deborah, additional, Gueugnon, Fabien, additional, Dalloneau, Emilie, additional, Baranek, Thomas, additional, Henry, Clémence, additional, Morello, Eric, additional, Renauld, Jean-Christophe, additional, Pichavant, Muriel, additional, Gosset, Philippe, additional, Courty, Yves, additional, Diot, Patrice, additional, and Si-Tahar, Mustapha, additional

Published
2015
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9. Pseudomonas aeruginosa proteolytically alters the interleukin 22-dependent lung mucosal defense.

Author

Guillon, Antoine, Brea, Deborah, Morello, Eric, Tang, Aihua, Jouan, Youenn, Ramphal, Reuben, Korkmaz, Brice, Perez-Cruz, Magdiel, Trottein, Francois, O'Callaghan, Richard J., Gosset, Philippe, and Si-Tahar, Mustapha

Subjects
*PSEUDOMONAS aeruginosa, *INTERLEUKINS, *MICROBIAL peptides, *EPITHELIAL cells, *CELL proliferation
Abstract

The IL-22 signaling pathway is critical for regulating mucosal defense and limiting bacterial dissemination. IL-22 is unusual among interleukins because it does not directly regulate the function of conventional immune cells, but instead targets cells at outer body barriers, such as respiratory epithelial cells. Consequently, IL-22 signaling participates in the maintenance of the lung mucosal barrier by controlling cell proliferation and tissue repair, and enhancing the production of specific chemokines and anti-microbial peptides.Pseudomonas aeruginosais a major pathogen of ventilator-associated pneumonia and causes considerable lung tissue damage. A feature underlying the pathogenicity of this bacterium is its capacity to persist and develop in the host, particularly in the clinical context of nosocomial lung infections. We aimed to investigate the ability ofP. auruginosato disrupt immune-epithelial cells cross-talk. We found thatP. aeruginosaescapes the host mucosal defenses by degrading IL-22, leading to severe inhibition of IL-22-mediated immune responses. We demonstratedin vitrothat, protease IV, a type 2 secretion system-dependent serine protease, is responsible for the degradation of IL-22 byP. aeruginosa. Moreover, the major anti-proteases molecules present in the lungs were unable to inhibit protease IV enzymatic activity. In addition, tracheal aspirates of patients infected byP. aeruginosacontain protease IV activity which further results in IL-22 degradation. This so far undescribed cleavage of IL-22 by a bacterial protease is likely to be an immune-evasion strategy that contributes toP. aeruginosa-triggered respiratory infections. [ABSTRACT FROM AUTHOR]

Published
2017
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10. Pseudomonas aeruginosaproteolytically alters the interleukin 22-dependent lung mucosal defense

Author

Guillon, Antoine, Brea, Deborah, Morello, Eric, Tang, Aihua, Jouan, Youenn, Ramphal, Reuben, Korkmaz, Brice, Perez-Cruz, Magdiel, Trottein, Francois, O'Callaghan, Richard J., Gosset, Philippe, and Si-Tahar, Mustapha

Abstract

ABSTRACTThe IL-22 signaling pathway is critical for regulating mucosal defense and limiting bacterial dissemination. IL-22 is unusual among interleukins because it does not directly regulate the function of conventional immune cells, but instead targets cells at outer body barriers, such as respiratory epithelial cells. Consequently, IL-22 signaling participates in the maintenance of the lung mucosal barrier by controlling cell proliferation and tissue repair, and enhancing the production of specific chemokines and anti-microbial peptides. Pseudomonas aeruginosais a major pathogen of ventilator-associated pneumonia and causes considerable lung tissue damage. A feature underlying the pathogenicity of this bacterium is its capacity to persist and develop in the host, particularly in the clinical context of nosocomial lung infections. We aimed to investigate the ability of P. auruginosato disrupt immune-epithelial cells cross-talk. We found that P. aeruginosaescapes the host mucosal defenses by degrading IL-22, leading to severe inhibition of IL-22-mediated immune responses. We demonstrated in vitrothat, protease IV, a type 2 secretion system-dependent serine protease, is responsible for the degradation of IL-22 by P. aeruginosa. Moreover, the major anti-proteases molecules present in the lungs were unable to inhibit protease IV enzymatic activity. In addition, tracheal aspirates of patients infected by P. aeruginosacontain protease IV activity which further results in IL-22 degradation. This so far undescribed cleavage of IL-22 by a bacterial protease is likely to be an immune-evasion strategy that contributes to P. aeruginosa-triggered respiratory infections.

Published
2017
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11. Neutrophils can disarm NK cell response through cleavage of NKp46

Author

Valayer, Alexandre, Brea, Deborah, Lajoie, Laurie, Avezard, Leslie, Combes-Soia, Lucie, Labas, Valerie, Korkmaz, Brice, Thibault, Gilles, Baranek, Thomas, and Si-Tahar, Mustapha

Abstract

Polymorphonuclear neutrophils (PMNs) can contribute to the regulation of the host immune response by crosstalk with innate and adaptive leukocytes, including NK cells. Mechanisms by which this immunoregulation process occurs remain incompletely understood. Here, we focused on the effect of human neutrophil-derived serine proteases on NKp46, a crucial activating receptor expressed on NK cells. We used flow cytometry, Western blotting, and mass spectrometry (MS) analysis to reveal that cathepsin G [CG; and not elastase or proteinase 3 (PR3)] induces a time- and concentration-dependent, down-regulatory effect on NKp46 expression through a restricted proteolytic mechanism. We also used a functional assay to demonstrate that NKp46 cleavage by CG severely impairs NKp46-mediated responses of NK cells, including IFN-? production and cell degranulation. Importantly, sputa of cystic fibrosis (CF) patients, which have high concentrations of CG, also alter NKp46 on NK cells. Hence, we have identified a new immunoregulatory mechanism of neutrophils that proteolytically disarms NK cell responses. Immuno-regulatory mechanism of PMNs that proteolytically disarms NK cell response.

Published
2017
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12. Tissue kallikrein regulates alveolar macrophage apoptosis early in influenza virus infection

Author

Yambasu A. Brewah, Thomas Baranek, Damien Sizaret, Fabien Gueugnon, Agnès Petit-Courty, Mélia Magnen, Mustapha Si-Tahar, Alison A. Humbles, Yves Courty, Université de Tours (UT), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), MedImmune, brea, deborah, and Gonzalez, Loïc

Subjects
0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], Tissue kallikrein, influenza virus, Madin Darby Canine Kidney Cells, Mice, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, kallikrein, Macrophage, Chemokine CCL5, Chemokine CCL2, Chemokine CCL3, Mice, Knockout, apoptosis, 3. Good health, Killer Cells, Natural, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, medicine.anatomical_structure, Tissue Kallikreins, Pulmonary and Respiratory Medicine, Proteases, Acute Lung Injury, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Respiratory Mucosa, macrophage, Biology, Lung injury, Virus, Cell Line, 03 medical and health sciences, Dogs, Orthomyxoviridae Infections, Physiology (medical), Macrophages, Alveolar, medicine, Animals, Humans, COPD, lung injury, Influenza A Virus, H3N2 Subtype, chemokine, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Biology, Kallikrein, Epithelium, Chemokine CXCL10, Mice, Inbred C57BL, 030104 developmental biology, A549 Cells, Immunology, Alveolar macrophage, epithelium, 030215 immunology
Abstract

International audience; Host cell proteases are involved in influenza pathogenesis. We examined the role of tissue kallikrein 1 (KLK1) by comparing wild-type (WT) and KLK1-deficient mice infected with influenza H3N2 virus. The levels of KLK1 in lung tissue and in bronchoalveolar lavage (BAL) fluid increased substantially during infection. KLK1 did not promote virus infectivity despite its trypsin-like activity, but it did decrease the initial virus load. We examined two cell types involved in the early control of pathogen infections, alveolar macrophages (AMs) and natural killer (NK) cells to learn more about the antiviral action of KLK1. Inactivating the Klk1 gene or treating WT mice with an anti-KLK1 monoclonal antibody to remove KLK1 activity accelerated the initial virus-induced apoptotic depletion of AMs. Intranasal instillation of deficient mice with recombinant KLK1 (rKLK1) reversed the phenotype. The levels of granulocyte-macrophage colony-stimulating factor in infected BAL fluid were significantly lower in KLK1-deficient mice than in WT mice. Treating lung epithelial cells with rKLK1 increased secretion of this factor known to enhance AM resistance to pathogen-induced apoptosis. The recruitment of NK cells to the air spaces peaked 3 days after infection in WT mice but not in KLK1-deficient mice, as did increases in several NK-attracting chemokines (CCL2, CCL3, CCL5, and CXCL10) in BAL. Chronic obstructive pulmonary disease (COPD) patients are highly susceptible to viral infection, and we observed that the KLK1 mRNA levels decreased with increasing COPD severity. Our findings indicate that KLK1 intervenes early in the antiviral defense modulating the severity of influenza infection. Decreased KLK1 expression in COPD patients could contribute to the worsening of influenza.

Published
2019
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13. TLR5 signalling is hyper-responsive in porcine cystic fibrosis airways epithelium

Author

Isabelle, Fleurot, Raquel, López-Gálvez, Pascal, Barbry, Antoine, Guillon, Mustapha, Si-Tahar, Andrea, Bähr, Nikolai, Klymiuk, Jean-Claude, Sirard, Ignacio, Caballero, Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gene Center and Center for Innovative Medical Models (CIMM), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Association Vaincre la Mucoviscidose (grants RF20150501357, RF20160501644 and RF20170502036), ANR-18-CE20-0024,PIGIMMUNITY,PIGIMMUNITY: une approche de biologie des systèmes pour stimuler la réponse innée chez le porc(2018), Infectiologie et Santé Publique [UMR ISP], Institut de pharmacologie moléculaire et cellulaire [IPMC], Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 [CEPR], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Ludwig Maximilian University [Munich] (LMU), CHU Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), brea, deborah, APPEL À PROJETS GÉNÉRIQUE 2018 - PIGIMMUNITY: une approche de biologie des systèmes pour stimuler la réponse innée chez le porc - - PIGIMMUNITY2018 - ANR-18-CE20-0024 - AAPG2018 - VALID, Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cystic Fibrosis, Swine, education, Cystic Fibrosis Transmembrane Conductance Regulator, respiratory system, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Epithelium, respiratory tract diseases, Toll-Like Receptor 5, Animals, Humans, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Lung, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Flagellin
Abstract

International audience; Excessive lung inflammation and airway epithelium damage are hallmarks of cystic fibrosis (CF) disease. It is unclear whether lung inflammation is related to an intrinsic defect in the immune response or to chronic infection. We aimed to determine whether TLR5-mediated response is defective in the CF airway epithelium. We used a newborn CF pig model to study intrinsic alterations in CF airway epithelium innate immune response. Airway epithelial cells (AECs) were stimulated with flagellin or lipopolysaccharide to determine responses specific for TLR5 and TLR4, respectively. We observed a significant increase in cytokine secretion when CF AECs were stimulated with flagellin compared to wild type (WT) AECs. These results were recapitulated when AECs were treated with an inhibitor of CFTR channel activity. We show that TLR5-signalling is altered in CF lung epithelium at birth. Modulation of TLR5 signalling could contribute to better control the excessive inflammatory response observed in CF lungs.

Published
2021
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14. Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors

Author

Emilie Barsac, Thierry Mallevaey, Loïc Gonzalez, Thomas Baranek, Christophe Paget, Carolina de Amat Herbozo, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT), University of Toronto, brea, deborah, Université de Toronto, Department of Biology, University of Toronto, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Gonzalez, Loïc, and PAGET, Christophe

Subjects
0301 basic medicine, Cancer Research, Solid cancer, immunoregulation, T cell, [SDV]Life Sciences [q-bio], Tumor immunity, Review, Biology, Major histocompatibility complex, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, solid cancer, protumor, medicine, γδT, tumor microenvironment, RC254-282, Tumor microenvironment, T-cell receptor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, NKT, cytokines, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, MAIT, unconventional T cells
Abstract

Simple Summary While the biology of unconventional T cells has been extensively studied in the context of infection, their role in tumor immunity has only recently emerged. In this review, we provide an overview of the current knowledge pointing towards protumoral functions of unconventional T cells in solid cancer. The tumor microenvironment factors that shape and control these deleterious properties are also reviewed. Finally, we discuss how these elements may be considered as future targets in cancer immunotherapy and the outstanding questions in the field. Abstract The vast majority of studies on T cell biology in tumor immunity have focused on peptide-reactive conventional T cells that are restricted to polymorphic major histocompatibility complex molecules. However, emerging evidence indicated that unconventional T cells, including γδ T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are also involved in tumor immunity. Unconventional T cells span the innate–adaptive continuum and possess the unique ability to rapidly react to nonpeptide antigens via their conserved T cell receptors (TCRs) and/or to activating cytokines to orchestrate many aspects of the immune response. Since unconventional T cell lineages comprise discrete functional subsets, they can mediate both anti- and protumoral activities. Here, we review the current understanding of the functions and regulatory mechanisms of protumoral unconventional T cell subsets in the tumor environment. We also discuss the therapeutic potential of these deleterious subsets in solid cancers and why further feasibility studies are warranted.

Published
2021
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15. Les métabokines, des médiateurs essentiels de l’immunité anti-infectieuse

Author

Déborah Bréa-Diakite, Mustapha Si-Tahar, Sarah Monard, Antoine Guillon, Adeline Cezard, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gonzalez, Loïc, Université de Tours (UT), brea, deborah, Université de Tours, and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV] Life Sciences [q-bio], 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Immunity, 030220 oncology & carcinogenesis, [SDV]Life Sciences [q-bio], General Medicine, Biology, Molecular biology, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 030304 developmental biology
Abstract

Metabolism and immunity have long been classified in distinct research fields; however, the concept of immunometabolism has recently highlighted their close relationship. Immune cells in an infectious context undergo a metabolic reprogramming that leads to the accumulation of metabolites. Some of these metabolites, called metabokines, play a crucial role in anti-infectious immunity by having immunoregulatory and antimicrobial defence properties. On the one hand, metabokines regulate the response of host immune cells by modulating intracellular signalling and/or inducing post-translational modifications of proteins. On the other hand, metabokines can directly or indirectly target pathogens by inhibiting microbial metabolic pathways, restoring the sensitivity of bacteria to antibiotics, and disrupting viral replication cycles. These discoveries on metabokine properties could pave the way for the development of innovative anti-infectious metabolic treatments., Longtemps cloisonnés dans des domaines de recherche distincts, métabolisme énergétique et immunité ont un lien étroit, récemment mis en exergue par le concept d’immunométabolisme. Dans un contexte infectieux, des reprogrammations métaboliques peuvent en effet survenir dans les cellules immunitaires et aboutir à l’accumulation de divers métabolites, dont certains, appelés métabokines, possèdent des propriétés inattendues d’immunorégulation et de défense antimicrobienne. Ils jouent un rôle crucial dans l’immunité anti-infectieuse, en régulant la réponse des cellules immunitaires de l’hôte, mais aussi en ciblant directement ou indirectement les microorganismes pathogènes.

Published
2021
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16. A Bioluminescent 3CLPro Activity Assay to Monitor SARS-CoV-2 Replication and Identify Inhibitors

Author

Xavier de Lamballerie, Manon Brailly, Yves L. Janin, Aymeric Hans, José-Carlos Valle-Casuso, Vincent Lotteau, Franck Touret, Mustapha Si-Tahar, Magalie Mazelier, Virginie Vasseur, Patrice Andre, Clémence Jacquemin, Pierre-Olivier Vidalain, Didier Decimo, Cyrille Mathieu, Branka Horvat, Antoine Nougairède, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Unité des Virus Emergents (UVE), Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie et Biocatalyse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT), Laboratoire de pathologie équine de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), The project was funded by an intramural CIRI grant (AO-6-2020) and ANR-CoronaPepStop (ANR-20-COVI-000) and Fondation de France to BH. This work was supported by INSERM through the REACTing (REsearch and ACTion targeting emerging infectious diseases) initiative. This work was supported by the European Virus Archive Global (EVA GLOBAL) funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No 871029. This work was supported by the Fondation de France 'call FLASH COVID-19', project TAMAC., We acknowledge World Reference Center for Emerging Viruses and Arboviruses (WRCEVA) and UTMB investigator, Pei Yong Shi for kindly providing recombinant icSARS-CoV-2-mNG virus based on 2019-nCoV/USA_WA1/2020 isolate. We thank Christian Drosten for providing the SARS-CoV-2 strain through EVA GLOBAL. We thank Pieter S. Hiemstra (Leiden University Medical Center (LUMC), Netherlands) for his advice with the culture of primary nasal epithelial cells. We thank Yves Jacob for the fruitful discussions. Part of the work was done in the Aix Marseille University antivirals drug design platform 'AD2P', ANR-20-COVI-0049,CoronaPepStop,Développement des peptides inhibiteurs de fusion contre l'infection à coronavirus(2020), European Project: 871029,H2020,H2020-INFRAIA-2019-1,EVA-GLOBAL(2020), 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), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT), Physiopathologie et épidémiologie des maladies équines (PhEED), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), brea, deborah, Développement des peptides inhibiteurs de fusion contre l'infection à coronavirus - - CoronaPepStop2020 - ANR-20-COVI-0049 - COVID-19 - VALID, European Virus Archive GLOBAL - EVA-GLOBAL - - H20202020-01-01 - 2023-12-31 - 871029 - VALID, 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), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
chemical screening, [SDV]Life Sciences [q-bio], viruses, Biology, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Virology, Luciferase, Setanaxib, BAY2402234, 030304 developmental biology, 0303 health sciences, Vidofludimus, NADPH oxidase, Drug discovery, SARS-CoV-2, Cellular Assay, HEK 293 cells, DHODH, IPPA-17-A04, antiviral, QR1-502, 3. Good health, [SDV] Life Sciences [q-bio], Drug repositioning, Infectious Diseases, Viral replication, Cell culture, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Vero cell, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Abstract

International audience; Our therapeutic arsenal against viruses is very limited and the current pandemic of SARS-CoV-2 highlights the critical need for effective antivirals against emerging coronaviruses. Cellular assays allowing a precise quantification of viral replication in high-throughput experimental settings are essential to the screening of chemical libraries and the selection of best antiviral chemical structures. To develop a reporting system for SARS-CoV-2 infection, we generated cell lines expressing a firefly luciferase maintained in an inactive form by a consensus cleavage site for the viral protease 3CLPro of coronaviruses, so that the luminescent biosensor is turned on upon 3CLPro expression or SARS-CoV-2 infection. This cellular assay was used to screen a metabolism-oriented library of 492 compounds to identify metabolic vulnerabilities of coronaviruses for developing innovative therapeutic strategies. In agreement with recent reports, inhibitors of pyrimidine biosynthesis were found to prevent SARS-CoV-2 replication. Among the top hits, we also identified the NADPH oxidase (NOX) inhibitor Setanaxib. The anti-SARS-CoV-2 activity of Setanaxib was further confirmed using ACE2-expressing human pulmonary cells Beas2B as well as human primary nasal epithelial cells. Altogether, these results validate our cell-based functional assay and the interest of screening libraries of different origins to identify inhibitors of SARS-CoV-2 for drug repurposing or development.

Published
2021
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17. Ten-year trends in intensive care admissions for respiratory infections in the elderly

Author

Leslie Grammatico-Guillon, Youenn Jouan, Pierre-François Dequin, Kimberly M. Shea, Mustapha Si-Tahar, Emmanuelle Rouve, Coralie Hermetet, Christophe Gaborit, Lucile Laporte, Antoine Guillon, Université de Tours (UT), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Boston University [Boston] (BU), brea, deborah, and Gonzalez, Loïc

Subjects
medicine.medical_specialty, Acute exacerbation of chronic obstructive pulmonary disease, Epidemiology, [SDV]Life Sciences [q-bio], Critical Care and Intensive Care Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, Elderly, law, Intensive care, Anesthesiology, Respiratory infection, medicine, Intensive care unit, 030212 general & internal medicine, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, medicine.disease, [SDV] Life Sciences [q-bio], Pneumonia, Emergency medicine, Diagnosis code, business
Abstract

Background The consequences of the ageing population concerning ICU hospitalisation need to be adequately described. We believe that this discussion should be disease specific. A focus on respiratory infections is of particular interest, because it is strongly associated with old age. Our objective was to assess trends in demographics over a decade among elderly patients admitted to the ICU for acute respiratory infections. Methods A cross-sectional study was performed between 2006 and 2015 based on hospital discharge databases in one French region (2.5 million inhabitants). Patients with acute respiratory infection were selected according to the specific ICD-10 diagnosis codes recorded, including acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and community-acquired pneumonia (CAP). We also identified comorbid conditions based on any significant ICD-10 secondary diagnoses adapted from the Charlson and Elixhauser indexes. Results A total of 98,381 hospital stays for acute respiratory infection were identified among the 3,856,785 stays over the 10-year period. The number of patients 75 y/o and younger increased 1.6-fold from 2006 to 2015, whereas the numbers of patients aged 85–89 and ≥ 90 y/o increased by 2.5- and 2.1-fold, respectively. Both CAP and AECOPD hospitalisations significantly increased for all age groups over the decade. ICU hospitalisations for respiratory infection increased 2.7-fold from 2006 to 2015 (p = 0.0002). The greatest increases in the use of ICU resources were for the 85–89 and ≥ 90 y/o groups, which corresponded to increases of 3.3- and 5.8-fold. Indeed, the proportion of patients hospitalized for respiratory infection in ICU that were elderly clearly grew during the decade: 11.3% were ≥ 85 y/o in 2006 versus 16.4% in 2015 (p

Published
2018
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18. Cigarette smoke induces overexpression of active human cathepsin S in lungs from current smokers with or without COPD

Author

Thomas Baranek, Agnès Petit-Courty, Andrea C. Schamberger, Fabien Lecaille, Ahlame Saidi, Pierre-Marie Andrault, Oliver Eickelberg, Thibault Chazeirat, Damien Sizaret, Mylène Wartenberg, Serge Guyétant, Elisabeth Hennen, Gilles Lalmanach, Justine Renault, Yves Courty, Claudia A. Staab-Weijnitz, Université de Tours (UT), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig-Maximilians-Universität München (LMU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), brea, deborah, Centre d'Etude des Pathologies Respiratoires (CEPR), UMR 1100. Equipe 2 'Mécanismes Protéolytiques dans l'Inflammation' (CEPR. Equipe 2), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Comprehensive Pneumology Center - Institute of Lung Biology and Disease (iLBD), German Center for Lung Research, Anatomie et cytologie pathologique [Tours], Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), INSERM, Université de Tours, Région Centre-Val de Loire (project BPCO-LYSE no. 2015103986), Deutsche Forschungsgemeinschaft (DFG) within the Research Training Group DFG GRK2338, Helmholtz Zentrum München = German Research Center for Environmental Health, Lalmanach, Gilles, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université de Tours, and Gonzalez, Loïc

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Male, Physiology, oxidation, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Respiratory Mucosa, smokers, medicine.disease_cause, Cigarette Smoking, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Cigarette smoking, Physiology (medical), Cigarette smoke, Medicine, Humans, COPD, cysteine protease, Cigarette Smoke, Copd, Cysteine Protease, Oxidation, Smokers, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cells, Cultured, Cathepsin S, Aged, Protease, business.industry, cigarette smoke, Epithelial Cells, Cell Biology, Middle Aged, medicine.disease, Cysteine protease, Cathepsins, 3. Good health, respiratory tract diseases, [SDV] Life Sciences [q-bio], Oxidative Stress, 030104 developmental biology, 030228 respiratory system, Case-Control Studies, Immunology, Female, business, Lung tissue, Oxidative stress
Abstract

International audience; Cigarette smoking has marked effects on lung tissue, including induction of oxidative stress, inflammatory cell recruitment, and a protease/antiprotease imbalance. These effects contribute to tissue remodeling and destruction resulting in loss of lung function in chronic obstructive pulmonary disease (COPD) patients. Cathepsin S (CatS) is a cysteine protease that is involved in the remodeling/degradation of connective tissue and basement membrane. Aberrant expression or activity of CatS has been implicated in a variety of diseases, including arthritis, cancer, cardiovascular, and lung diseases. However, little is known about the effect of cigarette smoking on both CatS expression and activity, as well as its role in smoking-related lung diseases. Here, we evaluated the expression and activity of human CatS in lung tissues from never-smokers and smokers with or without COPD. Despite the presence of an oxidizing environment, CatS expression and activity were significantly higher in current smokers (both non-COPD and COPD) compared with never-smokers, and correlated positively with smoking history. Moreover, we found that the exposure of primary human bronchial epithelial cells to cigarette smoke extract triggered the activation of P2X7 receptors, which in turns drives CatS upregulation. The present data suggest that excessive CatS expression and activity contribute, beside other proteases, to the deleterious effects of cigarette smoke on pulmonary homeostasis.

Published
2019
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19. Impact of the TAP-like transporter in antigen presentation and phagosome maturation

Author

Loredana Saveanu, Sha Tao, Mustapha Si-Tahar, Myriam Lawand, Ingo Drexler, Sebastian Montealegre, Thomas Baranek, Peter van Endert, Irini Evnouchidou, Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Gonzalez, Loïc, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut für Virologie, Philipps University, and brea, deborah

Subjects
0301 basic medicine, Proteasome Endopeptidase Complex, [SDV]Life Sciences [q-bio], Immunology, Antigen presentation, Major histocompatibility complex, Transporter, 03 medical and health sciences, Mice, 0302 clinical medicine, Cross-Priming, Antigen, Phagocytosis, Cell Line, Tumor, Phagosomes, MHC class I, Phagosome maturation, Animals, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Phagosome, Mice, Knockout, MHC class II, Antigen Presentation, Cross-presentation, biology, Chemistry, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Membrane Transport Proteins, Dendritic Cells, Cell biology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Protein Transport, 030104 developmental biology, Proteolysis, Peptide, biology.protein, ATP-Binding Cassette Transporters, MHC, Peptides, Dendritic cell, 030215 immunology, HeLa Cells
Abstract

International audience; Cross-presentation is thought to require transport of proteasome-generated peptides by the TAP transporters into MHC class I loading compartments for most antigens. However, a proteasome-dependent but TAP-independent pathway has also been described. Depletion of the pool of recycling cell surface MHC class I molecules available for loading with cross-presented peptides might partly or largely account for the critical role of TAP in cross-presentation of phagocytosed antigens. Here we examined a potential role of the homodimeric lysosomal TAP-like transporter in cross-presentation and in presentation of endogenous peptides by MHC class II molecules. We find that TAP-L is strongly recruited to dendritic cell phagosomes at a late stage, when internalized antigen and MHC class I molecules have been degraded or sorted away from phagosomes. Cross-presentation of a receptor-targeted antigen in vitro and of a phagocytosed antigen in vivo, as well as presentation of a cytosolic antigen by MHC class II molecules, is not affected by TAP-L deficiency. However, accumulation in vitro of a peptide optimally adapted to TAP-L selectivity in purified phagosomes is abolished by TAP-L deficiency. Unexpectedly, we find that TAP-L deficiency accelerates phagosome maturation, as reflected in increased Lamp2b recruitment and enhanced proteolytic degradation of phagocytosed antigen and in vitro transported peptides. Although additional experimentation will be required to definitely conclude on the role of TAP-L in transport of peptides presented by MHC class I and class II molecules, our data suggest that the principal role of TAP-L in dendritic cells may be related to regulation of phagosome maturation.

Published
2019
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20. Proteinase release from activated neutrophils in mechanically ventilated patients with non-COVID-19 and COVID-19 pneumonia

Author

Youenn Jouan, Antoine Guillon, Loïc Gonzalez, Sylvain Marchand-Adam, Brice Korkmaz, Seda Seren, Dieter E. Jenne, Adam Lesner, Irem Keleş, Christophe Paget, Thomas Baranek, Mustapha Si-Tahar, Lohann Derian, brea, deborah, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Yeditepe University, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Gdańsk (UG), Max Planck Institute of Neurobiology (MPIN), Max-Planck-Gesellschaft, PAGET, Christophe, and Gonzalez, Loïc

Subjects
Pulmonary and Respiratory Medicine, ARDS, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Neutrophils, [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Microbiology, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Agora, ComputingMilieux_MISCELLANEOUS, SARS-CoV-2, business.industry, COVID-19, medicine.disease, Respiration, Artificial, Research Letters, 3. Good health, [SDV] Life Sciences [q-bio], Pneumonia, 030228 respiratory system, Peptide Hydrolases, business
Abstract

Severe cases of pneumonia are frequently associated with acute respiratory distress syndrome (ARDS), which carries a mortality rate of about 40% [1]. Uncontrolled host inflammatory response in the lung is a key factor in the transition from pneumonia to ARDS, with alveolocapillary membrane disruption leading to interstitial and alveolar oedema [2]. Neutrophils are part of the innate immune system and are the first responders to local tissue damage and infection. Recruited neutrophils are considered important actors in lung tissue injury [3]. Indeed, their broad arsenal of antimicrobial weaponry can cause direct and indirect collateral damage. Neutrophil serine proteinases (NSPs), including elastase (NE), proteinase 3 (PR3) and cathepsin G (CatG), are released from activated cells and play a part in ARDS pathophysiology, as illustrated in both preclinical and clinical studies [4]. Thus, NSPs emerge as an untapped point for therapeutic interventions in pneumonia-induced ARDS [4]. These NSPs are readily synthesised in neutrophil precursors within the bone marrow and are converted into their active form by cathepsin C (CatC) [5]. They are stored together in cytoplasmic granules and secreted into the extracellular compartment upon stimulation [6]., COVID-19 ARDS is associated with release of biologically active neutrophil elastase-related proteinases to the airways and blood at a comparable level to non-COVID ARDS https://bit.ly/3nihveh

Published
2021
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21. Lack of FcRn Impairs Natural Killer Cell Development and Functions in the Tumor Microenvironment

Author

Castaneda, Diana Cadena, Dhommée, Christine, Baranek, Thomas, Dalloneau, Emilie, Lajoie, Laurie, Valayer, Alexandre, Arnoult, Christophe, Demattéi, Marie-Véronique, Fouquenet, Delphine, Parent, Christelle, Heuzé-Vourc'h, Nathalie, Gouilleux-Gruart, Valérie, Université de Tours (UT), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Canaux calciques , fonctions et pathologies, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Etude des Parasites Génétiques (LEPG), Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours (UT)-EA3856, Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-EA3856, Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), LAJOIE, Laurie, Université Francois Rabelais [Tours], and brea, deborah

Subjects
Lung Neoplasms, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], fcgrt knock-out, Immunology, Down-Regulation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Receptors, Fc, NK cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, anti-tumor immunity, Cell Degranulation, Statistics, Nonparametric, Interferon-gamma, Mice, CD107a, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Tumor Microenvironment, Animals, Neoplasm Metastasis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, IFN-γ, Original Research, Mice, Knockout, Histocompatibility Antigens Class I, Lysosome-Associated Membrane Glycoproteins, Cell Differentiation, [SDV] Life Sciences [q-bio], Killer Cells, Natural, Mice, Inbred C57BL, Disease Models, Animal, FcRn, [SDV.IMM]Life Sciences [q-bio]/Immunology, Transcytosis
Abstract

International audience; The neonatal Fc receptor (FcRn) is responsible for the recycling and transcytosis of IgG and albumin. FcRn level was found altered in cancer tissues and implicated in tumor immunosurveillance and neoplastic cell growth. However, the consequences of FcRn down-regulation in the anti-tumor immune response are not fully elucidated. By using the B16F10 experimental lung metastasis model in an FcRn-deficient microenvironment (FcRn-/- mice), we found lung metastasis associated with an abnormal natural killer (NK) cell phenotype. In FcRn-/- mice, NK cells were immature, as shown by their surface marker profile and their decreased ability to degranulate and synthesize interferon γ after chemical and IL-2 or IL-12, IL-15 and IL-18 activation. These new findings support the critical role of FcRn downregulation in the tumor microenvironment in anti-tumor immunity, via NK cell maturation and activation.

Published
2018
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22. FPR2: A Novel Promising Target for the Treatment of Influenza

Author

Marie-Christine Alessi, Béatrice Riteau, Mustapha Si-Tahar, Nicolas Cenac, Fibrinolyse et Pathologie Vasculaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), 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), Centre d'Etude des Pathologies Respiratoires, Transgénèse et Archivage d'Animaux Modèles - Centre d'Imagerie du Petit Animal (TAAM-CIPA), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), ANR-13-BSV3-0011, Fondation de France 00066467, Association Gregory Le Marchal RF20160501641, Institut de Recherche en Santé Digestive (IRSD ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation de France (Grant 00066467), Foundation pour la Mucoviscidose, Association Gregory Le Marchal (Grant No RF20160501641), SATT-Sud Est, ANR-13-BSV3-0011,HemoFlu,Rôle de l'hémostase dans les infections influenza(2013), brea, deborah, Blanc 2013 - Rôle de l'hémostase dans les infections influenza - - HemoFlu2013 - ANR-13-BSV3-0011 - Blanc 2013 - VALID, Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Transgenèse et archivage d'animaux modèles (TAAM), and Goletto, Marie-Hélène

Subjects
0301 basic medicine, FPR2, Microbiology (medical), grippe, Mini Review, [SDV]Life Sciences [q-bio], réponse immunitaire, lcsh:QR1-502, formyl peptide receptor, influenza, human, inflammation mediators, antiviral agents, Biology, Microbiology, lcsh:Microbiology, Virus, Pathogenesis, 03 medical and health sciences, Immune system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, pathogénèse, Receptor, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, 030102 biochemistry & molecular biology, Host (biology), Virology, Transmembrane protein, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Viral replication, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Annexin A1
Abstract

International audience; The Formyl-peptide receptor-2 (FPR2) is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses. FPR2 is also used by viruses for their own profit. Annexin A1, one of the multiple ligands of FPR2, is incorporated in the budding virus membrane of influenza A viruses (IAV). Thereby, once IAV infect a host cell, FPR2 is activated. FPR2-signaling leads to an increase in viral replication, a dysregulation of the host immune response and a severe disease. Conversely, experiments using FPR2 antagonists in a preclinical model of IAV infections in mice showed that blocking FPR2 protects animals from lethal infections. Thus, FPR2 represents a very attractive host target against influenza. In this review we will give an overview on the pathogenesis of influenza with a focus on the role of FPR2 and we will discuss the advantages of using FPR2 antagonists to treat the flu.

Published
2017
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23. Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

Author

Yves Courty, Jonathan M. Harris, Fabien Gueugnon, Thomas Baranek, Agnès Petit-Courty, Alison A. Humbles, Simon J. de Veer, Mustapha Si-Tahar, Mélia Magnen, Antoine Guillon, Virginie C. Thibault, brea, deborah, Université de Tours (UT), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Queensland University of Technology [Brisbane] (QUT), MedImmune, and Gonzalez, Loïc

Subjects
0301 basic medicine, Proteases, medicine.medical_treatment, viruses, [SDV]Life Sciences [q-bio], Immunology, Hemagglutinin Glycoproteins, Influenza Virus, Biology, Microbiology, Virus, influenza virus, 03 medical and health sciences, Influenza A Virus, H1N1 Subtype, Orthomyxoviridae Infections, Virology, medicine, Animals, Humans, Secretion, Cells, Cultured, Infectivity, Protease, Influenza A Virus, H3N2 Subtype, Body Weight, KLK5, Epithelial Cells, Kallikrein, Survival Analysis, Virus-Cell Interactions, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Insect Science, Host-Pathogen Interactions, Proteolysis, Kallikreins, proteases, Respiratory tract
Abstract

Hemagglutinin (HA) of influenza virus must be activated by proteolysis before the virus can become infectious. Previous studies indicated that HA cleavage is driven by membrane-bound or extracellular serine proteases in the respiratory tract. However, there is still uncertainty as to which proteases are critical for activating HAs of seasonal influenza A viruses (IAVs) in humans. This study focuses on human KLK1 and KLK5, 2 of the 15 serine proteases known as the kallikrein-related peptidases (KLKs). We find that their mRNA expression in primary human bronchial cells is stimulated by IAV infection. Both enzymes cleaved recombinant HA from several strains of the H1 and/or H3 virus subtype in vitro , but only KLK5 promoted the infectivity of A/Puerto Rico/8/34 (H1N1) and A/Scotland/20/74 (H3N2) virions in MDCK cells. We assessed the ability of treated viruses to initiate influenza in mice. The nasal instillation of only the KLK5-treated virus resulted in weight loss and lethal outcomes. The secretion of this protease in the human lower respiratory tract is enhanced during influenza. Moreover, we show that pretreatment of airway secretions with a KLK5-selective inhibitor significantly reduced the activation of influenza A/Scotland/20/74 virions, providing further evidence of its importance. Differently, increased KLK1 secretion appeared to be associated with the recruitment of inflammatory cells in human airways regardless of the origin of inflammation. Thus, our findings point to the involvement of KLK5 in the proteolytic activation and spread of seasonal influenza viruses in humans. IMPORTANCE Influenza A viruses (IAVs) cause acute infection of the respiratory tract that affects millions of people during seasonal outbreaks every year. Cleavage of the hemagglutinin precursor by host proteases is a critical step in the life cycle of these viruses. Consequently, host proteases that activate HA can be considered promising targets for the development of new antivirals. However, the specific proteases that activate seasonal influenza viruses, especially H3N2 viruses, in the human respiratory tract have remain undefined despite many years of work. Here we demonstrate that the secreted, extracellular protease KLK5 (kallikrein-related peptidase 5) is efficient in promoting the infectivity of H3N2 IAV in vitro and in vivo . Furthermore, we found that its secretion was selectively enhanced in the human lower respiratory tract during a seasonal outbreak dominated by an H3N2 virus. Collectively, our data support the clinical relevance of this protease in human influenza pathogenesis.

Published
2017
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24. Neutrophils can disarm NK cell response through cleavage of NKp46

Author

Valérie Labas, Déborah Bréa, Laurie Lajoie, Leslie Avezard, Thomas Baranek, Alexandre Valayer, Gilles Thibault, Lucie Combes-Soia, Brice Korkmaz, Mustapha Si-Tahar, Université de Tours (UT), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), INSERM, Universite Francois Rabelais de Tours, Conseil Regional Centre-Val de Loire (Flukiller), brea, deborah, Unite Mixte de Recherche 1100, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Francois Rabelais [Tours], Unite Mixte de Recherche 7292, Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Plateforme d'Analyse Intégrative des Biomolécules, Institut National de la Recherche Agronomique (INRA), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, neutrophile, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Proteases, proteolysis, Cathepsin G, Cell Degranulation, immunoregulation, Neutrophils, receptor, [SDV]Life Sciences [q-bio], mass spectrum analysis, Immunology, Cell, receptors, Down-Regulation, Biology, Neutrophil Activation, Flow cytometry, réponse cellulaire, 03 medical and health sciences, chemistry.chemical_compound, leucocyte polynucléaire, clivage proteolytique, 0302 clinical medicine, Immune system, spectrométrie de masse, medicine, Immunology and Allergy, Humans, Receptor, natural killer cells, medicine.diagnostic_test, Natural Cytotoxicity Triggering Receptor 1, Elastase, Cell Membrane, Cell Biology, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Killer Cells, Natural, 030104 developmental biology, medicine.anatomical_structure, chemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, K562 Cells, 030215 immunology
Abstract

Polymorphonuclear neutrophils (PMNs) can contribute to the regulation of the host immune response by crosstalk with innate and adaptive leukocytes, including NK cells. Mechanisms by which this immunoregulation process occurs remain incompletely understood. Here, we focused on the effect of human neutrophil-derived serine proteases on NKp46, a crucial activating receptor expressed on NK cells. We used flow cytometry, Western blotting, and mass spectrometry (MS) analysis to reveal that cathepsin G [CG; and not elastase or proteinase 3 (PR3)] induces a time- and concentration-dependent, down-regulatory effect on NKp46 expression through a restricted proteolytic mechanism. We also used a functional assay to demonstrate that NKp46 cleavage by CG severely impairs NKp46-mediated responses of NK cells, including IFN-γ production and cell degranulation. Importantly, sputa of cystic fibrosis (CF) patients, which have high concentrations of CG, also alter NKp46 on NK cells. Hence, we have identified a new immunoregulatory mechanism of neutrophils that proteolytically disarms NK cell responses.

Published
2016
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25. Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

Author

Antoine Guillon, Fabien Gueugnon, Yves Courty, Emilie Dalloneau, Déborah Bréa, Mustapha Si-Tahar, Thomas Baranek, Eric Morello, Muriel Pichavant, Clémence Henry, Patrice Diot, Youenn Jouan, Jean-Christophe Renauld, Philippe Gosset, Université de Tours (UT), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and brea, deborah

Subjects
Pulmonary and Respiratory Medicine, Proteases, beta-Defensins, Lipopolysaccharide, Neutrophils, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Blotting, Western, Real-Time Polymerase Chain Reaction, Sensitivity and Specificity, Sampling Studies, Statistics, Nonparametric, Microbiology, Interleukin 22, Mice, Pulmonary Disease, Chronic Obstructive, chemistry.chemical_compound, Immune system, medicine, Animals, Humans, Cells, Cultured, COPD, business.industry, Smoking, Interleukin, Epithelial Cells, Receptors, Interleukin, medicine.disease, Immunity, Innate, respiratory tract diseases, [SDV] Life Sciences [q-bio], Disease Models, Animal, Cytokine, Beta defensin, chemistry, Pseudomonas aeruginosa, Immunology, business, Biomarkers, Peptide Hydrolases
Abstract

Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infection-driven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations.

Published
2015
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