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4. SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance

Author

Robinot, Rémy, Hubert, Mathieu, de Melo, Guilherme Dias, Lazarini, Françoise, Bruel, Timothée, Smith, Nikaïa, Levallois, Sylvain, Larrous, Florence, Fernandes, Julien, Gellenoncourt, Stacy, Rigaud, Stéphane, Gorgette, Olivier, Thouvenot, Catherine, Trébeau, Céline, Mallet, Adeline, Duménil, Guillaume, Gobaa, Samy, Etournay, Raphaël, Lledo, Pierre-Marie, Lecuit, Marc, Bourhy, Hervé, Duffy, Darragh, Michel, Vincent, Schwartz, Olivier, and Chakrabarti, Lisa A.

Published
2021
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7. Hepatic stellate cell hypertrophy is associated with metabolic liver fibrosis

Author

Hoffmann, Céline, Djerir, Nour El Houda, Danckaert, Anne, Fernandes, Julien, Roux, Pascal, Charrueau, Christine, Lachagès, Anne-Marie, Charlotte, Frédéric, Brocheriou, Isabelle, Clément, Karine, Aron-Wisnewsky, Judith, Foufelle, Fabienne, Ratziu, Vlad, Hainque, Bernard, Bonnefont-Rousselot, Dominique, Bigey, Pascal, and Escriou, Virginie

Published
2020
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13. USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis

Author

Costa, Lionel, Corre, Sébastien, Michel, Valérie, Le Luel, Krysten, Fernandes, Julien, Ziveri, Jason, Jouvion, Grégory, Danckaert, Anne, Mouchet, Nicolas, da Silva Barreira, David, Torres, Javier, Camorlinga, Margarita, d'Elios, Mario Milco, Fiette, Laurence, de Reuse, Hilde, Galibert, Marie-Dominique, Touati, Eliette, Pathogenèse de Helicobacter - Helicobacter Pathogenesis, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP), Pathogénie des infections systémiques (Inserm U1002), Neuropathologie expérimentale - Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Descartes - Paris 5 (UPD5), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Instituto Mexicano del Seguro Social [Mexico City, Mexico] (IMSS), Università degli Studi di Firenze = University of Florence (UniFI), Institut Mutualiste de Montsouris (IMM), CHU Pontchaillou [Rennes], Université Paris Diderot, Ligue Contre le Cancer, Odyssey Reinsurance Company, FIS/IMSS/PROT/PRIO/13/027), Fondo de Investigacion en salud, IMSS, Mexico, West committee Ligue Nationale Contre le Cancer, UMS Biosit, We thank Sophie Vaulont (Institut Cochin, Paris, France) for Usf1-/- mice, Timothy C Wang (Columbia University, NY, USA) for providing us couples of INS-GAS mice and Joana Gomes and Celso Reis (I3S-IPATIMUP, Porto, Portugal) for MKN45 cells. We also thank Laurence Bernard-Touami and the Animal Housing ARCHE (UMS Biosit, https://biosit.univ-rennes1.fr, University of Rennes, France), and David Hardy and Magalie Tichit (Unit of Experimental Neuropathology, Institut Pasteur, Paris, France) for her technical help on the histology part and the UtechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging, ANR-10–INSB–04, Investments for the Future), both as a part of the FranceBioImaging infrastructure., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut Pasteur [Paris], Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 (UPD5), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Touati, Eliette, and Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID

Subjects
[SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, oncogenes, gastric cancer, [SDV]Life Sciences [q-bio], DNA damage, genetic instability, [SDV.CAN]Life Sciences [q-bio]/Cancer, helicobacter pylori infection, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

International audience; Objective - Design - Human gastric epithelial cell lines were infected with 7.13, exposed or not to a DNA-damaging agent camptothecin (CPT), to mimic a genetic instability context. We quantified the expression of , and their target genes, we determined their subcellular localisation by immunofluorescence and examined USF1/p53 interaction. and INS-GAS mice were used to strengthen the findings in vivo and patient data examined for clinical relevance. Results - In vivo we revealed the dominant role of USF1 in protecting gastric cells against -induced carcinogenesis and its impact on p53 levels. In vitro, delocalises USF1 into foci close to cell membranes. prevents USF1/p53 nuclear built up and relocates these complexes in the cytoplasm, thereby impairing their transcriptional function. also inhibits CPT-induced USF1/p53 nuclear complexes, exacerbating CPT-dependent DNA damaging effects. Conclusion - Our data reveal that the depletion of USF1 and its de-localisation in the vicinity of cell membranes are essential events associated to the genotoxic activity of infection, thus promoting gastric carcinogenesis. These findings are also of clinical relevance, supporting USF1 expression as a potential marker of GC susceptibility.

Published
2020

14. SARS-CoV-2 infection damages airway motile cilia and impairs mucociliary clearance

Author

Robinot, Rémy, primary, Hubert, Mathieu, additional, de Melo, Guilherme Dias, additional, Lazarini, Françoise, additional, Bruel, Timothée, additional, Smith, Nikaïa, additional, Levallois, Sylvain, additional, Larrous, Florence, additional, Fernandes, Julien, additional, Gellenoncourt, Stacy, additional, Rigaud, Stéphane, additional, Gorgette, Olivier, additional, Thouvenot, Catherine, additional, Trébeau, Céline, additional, Mallet, Adeline, additional, Duménil, Guillaume, additional, Gobaa, Samy, additional, Etournay, Raphaël, additional, Lledo, Pierre-Marie, additional, Lecuit, Marc, additional, Bourhy, Hervé, additional, Duffy, Darragh, additional, Michel, Vincent, additional, Schwartz, Olivier, additional, and Chakrabarti, Lisa A., additional

Published
2020
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15. Insights into amebiasis using a human3D‐intestinal model

Author

Aguilar‐Rojas, Arturo, primary, Castellanos‐Castro, Silvia, additional, Matondo, Mariette, additional, Gianetto, Quentin Giai, additional, Varet, Hugo, additional, Sismeiro, Odile, additional, Legendre, Rachel, additional, Fernandes, Julien, additional, Hardy, David, additional, Coppée, Jean‐Yves, additional, Olivo‐Marin, Jean‐Christophe, additional, and Guillen, Nancy, additional

Published
2020
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17. USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis

Author

Costa, Lionel, primary, Corre, Sébastien, additional, Michel, Valérie, additional, Le Luel, Krysten, additional, Fernandes, Julien, additional, Ziveri, Jason, additional, Jouvion, Gregory, additional, Danckaert, Anne, additional, Mouchet, Nicolas, additional, Da Silva Barreira, David, additional, Torres, Javier, additional, Camorlinga, Margarita, additional, D'Elios, Mario Milco, additional, Fiette, Laurence, additional, De Reuse, Hilde, additional, Galibert, Marie-Dominique, additional, and Touati, Eliette, additional

Published
2019
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18. Helicobacter pylori targets mitochondrial import and components of mitochondrial DNA replication machinery through an alternative VacA-dependent and a VacA-independent mechanisms

Author

Chatre, Laurent, Fernandes, Julien, Michel, Valérie, Fiette, Laurence, Avé, Patrick, Arena, Giuseppe, Jain, Utkarsh, Haas, Rainer, Wang, Timothy C., Ricchetti, Miria, Touati, Eliette, Cellules Souches et Développement / Stem Cells and Development, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pathogenèse de Helicobacter, Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Histotechnologie et Pathologie, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Ludwig-Maximilians-Universität München (LMU), College of Physicians and Surgeons, Columbia University [New York], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Touati, Eliette

Subjects
Cytosol/metabolism, DNA Replication, Microbiologie [F11] [Sciences du vivant], Helicobacter Infections/metabolism/microbiology, Helicobacter pylori/metabolism, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], DNA, Mitochondrial, Models, Biological, Article, Cell Line, Helicobacter Infections, Mice, Cytosol, DNA, Mitochondrial/metabolism, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bacterial Proteins, Mitochondria/metabolism, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, Microbiology [F11] [Life sciences], lcsh:Science, DNA-Binding Proteins/metabolism, Helicobacter pylori, Bacterial Proteins/metabolism, lcsh:R, High Mobility Group Proteins, bacterial infections and mycoses, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, High Mobility Group Proteins/metabolism, digestive system diseases, DNA Polymerase gamma, Mitochondria, DNA Polymerase gamma/metabolism, DNA-Binding Proteins, Protein Transport, bacteria, lcsh:Q, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Mitochondrial ADP, ATP Translocases/metabolism, Mitochondrial ADP, ATP Translocases
Abstract

International audience; Targeting mitochondria is a powerful strategy for pathogens to subvert cell physiology and establish infection. Helicobacter pylori is a bacterial pathogen associated with gastric cancer development that is known to target mitochondria directly and exclusively through its pro-apoptotic and vacuolating cytotoxin VacA. By in vitro infection of gastric epithelial cells with wild-type and VacA-deficient H. pylori strains, treatment of cells with purified VacA proteins and infection of a mouse model, we show that H. pylori deregulates mitochondria by two novel mechanisms, both rather associated with host cell survival. First, early upon infection VacA induces transient increase of mitochondrial translocases and a dramatic accumulation of the mitochondrial DNA replication and maintenance factors POLG and TFAM. These events occur when VacA is not detected intracellularly, therefore do not require the direct interaction of the cytotoxin with the organelle, and are independent of the toxin vacuolating activity. In vivo, these alterations coincide with the evolution of gastric lesions towards severity. Second, H. pylori also induces VacA-independent alteration of mitochondrial replication and import components, suggesting the involvement of additional H. pylori activities in mitochondria-mediated effects. These data unveil two novel mitochondrial effectors in H. pylori-host interaction with links on gastric pathogenesis.

Published
2017

19. Insights into amebiasis using a human 3D‐intestinal model.

Author

Aguilar‐Rojas, Arturo, Castellanos‐Castro, Silvia, Matondo, Mariette, Gianetto, Quentin Giai, Varet, Hugo, Sismeiro, Odile, Legendre, Rachel, Fernandes, Julien, Hardy, David, Coppée, Jean‐Yves, Olivo‐Marin, Jean‐Christophe, and Guillen, Nancy

Subjects
ENTAMOEBA histolytica, INTESTINAL infections, ADHERENS junctions, TIGHT junctions, COMMUNICABLE diseases, TISSUE engineering
Abstract

Entamoeba histolytica is the causative agent of amebiasis, an infectious disease targeting the intestine and the liver in humans. Two types of intestinal infection are caused by this parasite: silent infection, which occurs in the majority of cases, and invasive disease, which affects 10% of infected persons. To understand the intestinal pathogenic process, several in vitro models, such as cell cultures, human tissue explants or human intestine xenografts in mice, have been employed. Nevertheless, our knowledge on the early steps of amebic intestinal infection and the molecules involved during human–parasite interaction is scarce, in part due to limitations in the experimental settings. In the present work, we took advantage of tissue engineering approaches to build a three‐dimensional (3D)‐intestinal model that is able to replicate the general characteristics of the human colon. This system consists of an epithelial layer that develops tight and adherens junctions, a mucus layer and a lamina propria‐like compartment made up of collagen containing macrophages and fibroblast. By means of microscopy imaging, omics assays and the evaluation of immune responses, we show a very dynamic interaction between E. histolytica and the 3D‐intestinal model. Our data highlight the importance of several virulence markers occurring in patients or in experimental models, but they also demonstrate the involvement of under described molecules and regulatory factors in the amoebic invasive process. [ABSTRACT FROM AUTHOR]

Published
2020
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24. A simple, inexpensive and multi‐scale 3‐D fluorescent test sample for optical sectioning microscopies

Author

Jennifer Corridon, Adi Salomon, Aaron Au, Julien Fernandes, Christopher M. Yip, Thierry Bastien, Ilya Olevsko, Kaitlin Szederkenyi, Brigitte Delhomme, Martin Oheim, Bar-Ilan University [Israël], Saints-Pères Paris Institute for Neurosciences (SPPIN - UMR 8003), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Toronto, Biomedtech Facilities (UMS 2009 / US36), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Institut Pasteur [Paris] (IP), Spectral and Airyscan confocal micrographs were taken on microscopes of the imaging core facility (CNRS UMS 2009, INSERM US 36, BioMedTech Facilities). Marcoscopic light-sheet images were acquired at UtechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging, ANR-10-INBS-04, Investments for the Future). AS acknowledges support from the French Ministry of Foreign Affairs and the French Embassy in Tel Aviv (Chateaubriand fellowship). KS is the laureate of a joint CNRS-U Toronto PhD fellowship. This study was financed by the CNRS, the University of Paris, the Israeli Science Foundation (ISF, grant 1231/19), U Toronto and the European Union (H2020 Eureka! Eurostars, 'NanoScale,' E!12848, to MO & AS). The authors are grateful for mobility support from a Franco-Israeli CNRS-LIA, 'ImagiNano,' and the FranceBioImaging large-scale national infrastructure initiative (FBI, ANR-10-INSB-04, Investments for the future)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Fernandes, Julien, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), and Institut Pasteur [Paris]

Subjects
Histology, Materials science, Microscope, Optical sectioning, [SPI.OPTI] Engineering Sciences [physics]/Optics / Photonic, Sample (material), 02 engineering and technology, multi-modal, Dichroic glass, law.invention, 03 medical and health sciences, 0302 clinical medicine, Optics, law, Microscopy, Image Processing, Computer-Assisted, Fluorescence microscope, Calibration, quality control, Instrumentation, standardization, business.industry, Histological Techniques, Resolution (electron density), 030206 dentistry, 021001 nanoscience & nanotechnology, calibration, Sample (graphics), Metrology, Medical Laboratory Technology, metrology, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, fluorescence, Anatomy, 0210 nano-technology, business
Abstract

Fluorescence standards allow for quality control and for the comparison of data sets across instruments and laboratories in applications of quantitative fluorescence. For example, users of microscopy core facilities expect a homogenous and time-invariant illumination and a uniform detection sensitivity, which are prerequisites for quantitative imaging analysis, particle tracking or fluorometric pH or Ca2+-concentration measurements. Similarly, confirming the three-dimensional (3-D) resolution of optical sectioning micro-scopes prior to volumetric reconstructions calls for a regular calibration with a standardised point source. Typically, the test samples required for such calibration measurements are different ones, and they depend much on the very microscope technique used. Also, the ever-increasing choice among these techniques increases the demand for comparison and metrology across instruments. Here, we advocate and demonstrate the multiple uses of a surprisingly versatile and simple 3-D test sample that can complement existing and much more expensive calibration samples: simple commercial tissue paper labelled with a fluorescent highlighter pen. We provide relevant sample characteristics and show examples ranging from the sub-µm to cm scale, acquired on epifluorescence, confocal, image scanning, two-photon (2P) and light-sheet microscopes.Graphical abstractPyranine-labeled tissue paper, imaged upon 405-nm epifluorescence excitation through a 455LP LP dichroic and 465LP emission filter. Objective ×20/NA0.25. Overlaid are the normalised absorbance (dashed) and emission spectra (through line), respectively. In the present work we show that this “primitive” and inexpensive three-dimensional (3-D) test sample is a surprisingly versatile and powerful tool for quality assessment, comparison across microscopes as well as routine metrology for optical sectioning techniques, both for research labs and imaging core facilities.Research highlights-highlighter-pen marked tissue paper is a surprisingly powerful and versatile test sample for 3-D fluorescence microscopies-standard tissue paper presents features ranging from 400 nm to centimetres-our sample can simultaneously be used for testing intensity, field homogeneity, resolution, optical sectioning and image contrast-it is easy to prepare, versatile, photostable and inexpensive

Published
2021

25. Penetration of the Human Pulmonary Epithelium by Aspergillus fumigatus Hyphae

Author

Rémi Beau, Pierre Mordant, Julien Fernandes, Marina Pretolani, Fatima Hamidi, Amira Boukkerou, Remi Leborgne, Yves Castier, Jean-Paul Latgé, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Fibrose Inflammation Remodelage [Hôpitaux Universitaires Paris Nord Val de Seine] (DHU FIRE ), Hôpitaux Universitaires Paris Nord Val de Seine, ImagoSeine, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Aspergillus, Institut Pasteur [Paris], Service de Chirurgie Thoracique et Vasculaire [Hôpital Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was funded by grant 'Aspergillus' from Sanofi-Aviesan. The ImagoSeine facility at the Jacques Monod Institute (Paris, France) is supported by the French National Research Agency (ANR-10-INBS-04), 'Investments for the Future' program. The PBI-C2RT, Institut Pasteur (Paris, France) is supported by the French National Research Agency (ANR-10-INBS-04-01 and ANR-11-IDEX-0005-02)., We are grateful to the ImagoSeine facility at the Jacques Monod Institute (Paris), the PBI-CITech, Institut Pasteur (Paris), the Cellular and Tissue imaging plateform of the CRI (Inflammation Research Center), and the Investissement d’Avenir - Program, Laboratoire d’Excellence, INFLAMEX. We also thank Pascal Roux (Imagopole-CITech, Institut Pasteur) for his precious advice and VK Aimanianda and Ian Hooper for a careful revision of this manuscript., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Fernandes, Julien, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, Hypha, Cell Culture Techniques, Hyphae, Aspergillosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Microbiology, Aspergillus fumigatus, Conidium, lung, 03 medical and health sciences, Microscopy, Electron, Transmission, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, A fumigatus, medicine, Humans, Immunology and Allergy, aspergillosis, skin and connective tissue diseases, Cells, Cultured, Actin, ComputingMilieux_MISCELLANEOUS, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Microscopy, Confocal, Lung, biology, Chemistry, fungi, Epithelial Cells, respiratory system, medicine.disease, biology.organism_classification, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Epithelium, 3. Good health, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, mycology, Respiratory epithelium, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, epithelium
Abstract

Background The airway epithelium is the first barrier interacting with Aspergillus fumigatus conidia after their inhalation, suggesting that this structure functions as point of entry of this fungus to initiate pulmonary aspergillosis. Methods To study epithelial entry by A fumigatus, primary human reconstituted pseudostratified epithelium cultured in air-liquid interface as well as bronchial epithelial cell monolayers were infected with conidia. Results Under these experimental conditions, we found that A fumigatus hyphae traversed the bronchial epithelium through a mechanism involving the recruitment of actin, which formed a tunnel that allows hyphae to enter the cells without disturbing their integrity. Conclusions These findings describe a new mechanism by which A fumigatus hyphae penetrate the airway epithelial barrier and can infect its human host.

Published
2018

26. USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis.

Author

Costa L, Corre S, Michel V, Le Luel K, Fernandes J, Ziveri J, Jouvion G, Danckaert A, Mouchet N, Da Silva Barreira D, Torres J, Camorlinga M, D'Elios MM, Fiette L, De Reuse H, Galibert MD, and Touati E

Subjects
Animals, Cell Line, DNA Damage, Genomic Instability, Humans, Mice, Proteasome Endopeptidase Complex metabolism, Ubiquitination, Carcinogenesis genetics, Carcinogenesis metabolism, Gastric Mucosa metabolism, Gastric Mucosa microbiology, Gastric Mucosa pathology, Helicobacter Infections metabolism, Helicobacter pylori metabolism, Helicobacter pylori pathogenicity, Stomach Neoplasms genetics, Stomach Neoplasms metabolism, Stomach Neoplasms microbiology, Tumor Suppressor Protein p53 genetics, Upstream Stimulatory Factors metabolism
Abstract

Objective: Helicobacter pylori ( Hp ) is a major risk factor for gastric cancer (GC). Hp promotes DNA damage and proteasomal degradation of p53, the guardian of genome stability. Hp reduces the expression of the transcription factor USF1 shown to stabilise p53 in response to genotoxic stress. We investigated whether Hp -mediated USF1 deregulation impacts p53-response and consequently genetic instability. We also explored in vivo the role of USF1 in gastric carcinogenesis., Design: Human gastric epithelial cell lines were infected with Hp 7.13, exposed or not to a DNA-damaging agent camptothecin (CPT), to mimic a genetic instability context. We quantified the expression of USF1 , p53 and their target genes, we determined their subcellular localisation by immunofluorescence and examined USF1/p53 interaction. Usf1 -/- and INS-GAS mice were used to strengthen the findings in vivo and patient data examined for clinical relevance., Results: In vivo we revealed the dominant role of USF1 in protecting gastric cells against Hp -induced carcinogenesis and its impact on p53 levels. In vitro, Hp delocalises USF1 into foci close to cell membranes. Hp prevents USF1/p53 nuclear built up and relocates these complexes in the cytoplasm, thereby impairing their transcriptional function. Hp also inhibits CPT-induced USF1/p53 nuclear complexes, exacerbating CPT-dependent DNA damaging effects., Conclusion: Our data reveal that the depletion of USF1 and its de-localisation in the vicinity of cell membranes are essential events associated to the genotoxic activity of Hp infection, thus promoting gastric carcinogenesis. These findings are also of clinical relevance, supporting USF1 expression as a potential marker of GC susceptibility., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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27. Helicobacter pylori targets mitochondrial import and components of mitochondrial DNA replication machinery through an alternative VacA-dependent and a VacA-independent mechanisms.

Author

Chatre L, Fernandes J, Michel V, Fiette L, Avé P, Arena G, Jain U, Haas R, Wang TC, Ricchetti M, and Touati E

Subjects
Animals, Cell Line, Cytosol metabolism, DNA Polymerase gamma metabolism, DNA-Binding Proteins metabolism, Helicobacter Infections metabolism, Helicobacter Infections microbiology, High Mobility Group Proteins metabolism, Humans, Mice, Mitochondrial ADP, ATP Translocases metabolism, Models, Biological, Protein Transport, Bacterial Proteins metabolism, DNA Replication, DNA, Mitochondrial metabolism, Helicobacter pylori metabolism, Mitochondria metabolism
Abstract

Targeting mitochondria is a powerful strategy for pathogens to subvert cell physiology and establish infection. Helicobacter pylori is a bacterial pathogen associated with gastric cancer development that is known to target mitochondria directly and exclusively through its pro-apoptotic and vacuolating cytotoxin VacA. By in vitro infection of gastric epithelial cells with wild-type and VacA-deficient H. pylori strains, treatment of cells with purified VacA proteins and infection of a mouse model, we show that H. pylori deregulates mitochondria by two novel mechanisms, both rather associated with host cell survival. First, early upon infection VacA induces transient increase of mitochondrial translocases and a dramatic accumulation of the mitochondrial DNA replication and maintenance factors POLG and TFAM. These events occur when VacA is not detected intracellularly, therefore do not require the direct interaction of the cytotoxin with the organelle, and are independent of the toxin vacuolating activity. In vivo, these alterations coincide with the evolution of gastric lesions towards severity. Second, H. pylori also induces VacA-independent alteration of mitochondrial replication and import components, suggesting the involvement of additional H. pylori activities in mitochondria-mediated effects. These data unveil two novel mitochondrial effectors in H. pylori-host interaction with links on gastric pathogenesis.

Published
2017
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