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1. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection

Author

Gabriele Missale, Valeria Barili, Amalia Penna, Carolina Boni, Manuela Ferracin, Giovanna Forleo, Greta Acerbi, Giuseppe Pedrazzi, Alessandra Orlandini, Marzia Rossi, Simone Ottonello, Chiara Romualdi, Massimo Levrero, Marco Massari, Francesca Guerrieri, Cristina Mori, Alessandra Zecca, Anita Filippi, Barbara Montanini, Elisa Negri, Paola Fisicaro, Andrea Vecchi, Marco Pesci, Carlo Ferrari, Bodescot, Myriam, Host and viral factors in acute hepatitis C - HEPACUTE - - EC:FP7:HEALTH2010-11-01 - 2014-04-30 - 260844 - VALID, Department of Medicine and Surgery [Parme, Italie], Università degli studi di Parma = University of Parma (UNIPR), Unit of Infectious Diseases and Hepatology [Parme, Italie], Laboratory of Viral Immunopathology [Parme, Italie], Azienda Ospedaliero-Universitaria of Parma [Parme, Italie]-Azienda Ospedaliero-Universitaria of Parma [Parme, Italie], Biomolecular, Genomic and Biocomputational Sciences Unit [Parme, Italie], Department of Chemistry, Life Sciences and Environmental Sustainability [Parme, Italie], Università degli studi di Parma = University of Parma (UNIPR)-Università degli studi di Parma = University of Parma (UNIPR), Biopharmanet-Tec [Parme, Italie], Department of Biology [Padoue, Italie], Università degli Studi di Padova = University of Padua (Unipd), Department of Experimental, Diagnostic and Specialty Medicine [Bologne, Italie] (DIMES), University of Bologna/Università di Bologna, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Unit of Neuroscience [Parme, Italie], Robust Statistics Academy [Parme, Italie] (Ro.S.A.), Università degli studi di Parma = University of Parma (UNIPR)-Università degli studi di Parma = University of Parma (UNIPR)-Robust Statistics Academy [Parme, Italie] (Ro.S.A.), Unit of Infectious Diseases [Reggio d'Émilie, Italie], IRCCS-Azienda Ospedaliera S. Maria Nuova [Reggio d'Émilie, Italie], Service d'Hépatologie et de Gastroentérologie [Lyon], Hospices Civils de Lyon (HCL), Center for Life Nano Science [Rome, Italie], Istituto Italiano di Tecnologia [Rome, Italie] (IIT), This work also benefited from support by the Biotechnology Interuniversity Consortium (CIB) and the bioinformatics expertize framework available within the COMP-HUB Initiative, funded by the ‘Departments of Excellence’ program of the Italian Ministry for Education, University and Research (MIUR, 2018–2022). This work was supported by the European Commission grant HepAcute (FP7-HEALTH-2010), by a grant from Regione Emilia-Romagna, Italy (Programma di Ricerca Regione-Università 2010–2012, PRUa1RI-2012-006 to C.F., by a FIRB grant (RBAP10TPXK to C.F.) from the Italian Ministry of Education, University and Research (MIUR to C.F.), by a grant from 'Agence Nationale pour la Recherche sur le SIDA et les hepatites virales' (ANRS) to M.L. (n. ECTZ66014) and by a grant from the Agence National de la Recherche (ANR@TRACTION) to M.L., European Project: 260844,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,HEPACUTE(2010), Barili V., Fisicaro P., Montanini B., Acerbi G., Filippi A., Forleo G., Romualdi C., Ferracin M., Guerrieri F., Pedrazzi G., Boni C., Rossi M., Vecchi A., Penna A., Zecca A., Mori C., Orlandini A., Negri E., Pesci M., Massari M., Missale G., Levrero M., Ottonello S., Ferrari C., University of Parma = Università degli studi di Parma [Parme, Italie], University of Parma = Università degli studi di Parma [Parme, Italie]-University of Parma = Università degli studi di Parma [Parme, Italie], University of Padova [Padoue, Italie], University of Bologna, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Parma = Università degli studi di Parma [Parme, Italie]-University of Parma = Università degli studi di Parma [Parme, Italie]-Robust Statistics Academy [Parme, Italie] (Ro.S.A.)

Subjects
0301 basic medicine, Transcription, Genetic, General Physics and Astronomy, Ataxia Telangiectasia Mutated Proteins, CD8-Positive T-Lymphocytes, Lymphocyte Activation, medicine.disease_cause, Epigenesis, Genetic, 0302 clinical medicine, Cytotoxic T cell, Gene Regulatory Networks, lcsh:Science, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Principal Component Analysis, Multidisciplinary, Molecular medicine, Infection, Molecular medicine, Immunological surveillance, Middle Aged, Hepatitis C, Mitochondria, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Histone methyltransferase, Acute Disease, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Histone Methyltransferases, Infection, Signal Transduction, Adult, Adolescent, T cell, Hepatitis C virus, Science, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Antiviral Agents, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Downregulation and upregulation, medicine, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Aged, Gene Expression Profiling, Immunological surveillance, General Chemistry, Chronic infection, Glucose, 030104 developmental biology, T cell differentiation, Chronic Disease, Cancer research, lcsh:Q, Tumor Suppressor Protein p53, CD8
Abstract

Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer., Here, the authors report that exhausted HCV-specific CD8+ T cells are marked by upregulation of p53 signaling already detectable in an early phase of chronic HCV infection and by a later development of a repressive chromatin state, and show that chemical targeting of these pathways improves CD8+ T cell metabolism and antiviral function.

Published
2020
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2. Enteric delivery of regenerating family member 3 alpha alters the intestinal microbiota and controls inflammation in mice with colitis

Author

Marion, Darnaud, Alexandre, Dos Santos, Patrick, Gonzalez, Sandrine, Augui, Claire, Lacoste, Christophe, Desterke, Gert, De Hertogh, Emma, Valentino, Emilie, Braun, Jinzi, Zheng, Raphael, Boisgard, Christel, Neut, Laurent, Dubuquoy, Franck, Chiappini, Didier, Samuel, Patricia, Lepage, Francesca, Guerrieri, Joel, Doré, Christian, Bréchot, Nicolas, Moniaux, Jamila, Faivre, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Catholique de Louvain = Catholic University of Louvain (UCL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, Lille Inflammation Research International Center - U 995 (LIRIC), 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), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), Istituto Italiano di Tecnologia (IIT), Institut Pasteur [Paris], Fondation ARC pour la Recherche sur le Cancer [PJA 20111203952, PJA 20131200221, PJA 20141202048], Association pour la Recherche sur le Cancer Fellowship [R12036LL], Institut National du Cancer, OSEO-BPI Programme d'Investissements d'Avenir (IMODI consortium) [R14035LB], OSEO-BPI Programme d'Investissements d'Avenir (HECAM consortium) [R15065LH], European Project: 259743,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,MODHEP(2011), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), ProdInra, Migration, and Systems biology of liver cancer: an integrative genomic-epigenomic approach - MODHEP - - EC:FP7:HEALTH2011-01-01 - 2016-06-30 - 259743 - VALID

Subjects
Time Factors, LPS, [SDV.IMM] Life Sciences [q-bio]/Immunology, Colon, [SDV]Life Sciences [q-bio], IBD, Mice, Transgenic, Pancreatitis-Associated Proteins, Animals, Humans, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Microbial Viability, Mouse Model, Bacteria, Dextran Sulfate, Fecal Microbiota Transplantation, Colitis, Gastrointestinal Microbiome, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Disease Models, Animal, Oxidative Stress, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Trinitrobenzenesulfonic Acid, Hepatocytes, [SDV.IMM]Life Sciences [q-bio]/Immunology, Reactive Oxygen Species
Abstract

International audience; BACKGROUND & AIMS: Paneth cell dysfunction causes deficiencies in intestinal C-type lectins and antimicrobial peptides, which leads to dysbiosis of the intestinal microbiota, alters the mucosal barrier, and promotes development of inflammatory bowel diseases. We investigated whether transgenic (TG) expression of the human regenerating family member 3 alpha gene (REG3A) alters the fecal microbiota and affects development of colitis in mice. METHODS: We performed studies with C57BL/6 mice that express human regenerating family member 3 alpha (hREG3A) in hepatocytes, via the albumin gene promoter. In these mice, hREG3A travels via the bile to the intestinal lumen. Some mice were given dextran sodium sulfate (DSS) to induce colitis. Feces were collected from mice and the composition of the microbiota was analyzed by 16S ribosomal RNA sequencing. The fecal microbiome was also analyzed from mice that express only 1 copy of human REG3A transgene but were fed feces from control mice (not expressing hREG3A) as newborns. Mice expressing hREG3A were monitored for DSS-induced colitis after co-housing or feeding feces from control mice. Colitis was induced in another set of control and hREG3A-TG mice by administration of trinitrobenzene sulfonic acid; some mice were given intrarectal injections of the hREG3A protein. Colon tissues were collected from mice and analyzed by histology and immunohistochemistry to detect mucin 2, as well as by 16S ribosomal RNA fluorescence in situ hybridization, transcriptional analyses, and quantitative polymerase chain reaction. We measured levels of reactive oxygen species (ROS) in bacterial cultures and fecal microbiota using 20,70-dichloro-fluorescein diacetate and flow cytometry. RESULTS: The fecal microbiota of mice that express hREG3A had a significant shift in composition, compared with control mice, with enrichment of Clostridiales (Ruminococcaceae, Lachnospiraceae) and depletion of Bacteroidetes (Prevotellaceae); the TG mice developed less-severe colitis following administration of DSS than control mice, associated with preserved gut barrier integrity and reduced bacterial translocation, epithelial inflammation, and oxidative damage. A similar shift in the composition of the fecal microbiota occurred after a few months in TG mice heterozygous for REG3A that harbored a wild-type maternal microbiota at birth; these mice developed less-severe forms of colitis following DSS administration. Cohoused and germ-free mice fed feces from REG3A-TG mice and given DSS developed less-severe forms of colitis and had reduced lipopolysaccharide activation of the toll-like receptor 4 and increased survival times compared with mice not fed feces from REG3A-TG mice. REG3A TG mice developed only mild colonic inflammation after exposure to 2,4,6-trinitrobenzene sulfonic acid, compared with control mice. Control mice given intrarectal hREG3A and exposed to 2,4,6-trinitrobenzene sulfonic acid showed less colon damage and inflammation than mice not given intrarectal hREG3A. Fecal samples from REG3A-TG mice had lower levels of ROS than feces from control mice during DSS administration. Addition of hREG3A to bacterial cultures reduced levels of ROS and increased survival of oxygen-sensitive commensal bacteria (Faecalibacterium prausnitzii and Roseburia intestinalis). CONCLUSIONS: Mice with hepatocytes that express hREG3A, which travels to the intestinal lumen, are less sensitive to colitis than control mice. We found hREG3A to alter the colonic microbiota by decreasing levels of ROS. Fecal microbiota from REG3A-TG mice protect non-TG mice from induction of colitis. These findings indicate a role for reduction of oxidative stress in preserving the gut microbiota and its ability to prevent inflammation.

Published
2018
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