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1. Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort

Author

Qian Zhang, Paul Bastard, Haiguo Wu, Adrian Gervais, Seiamak Bahram, Sylvain Mayeur, Sharvari Gujja, Anne Thomas, Alexandre Lederle, Julie Helms, Christiane Moog, Xavier Mariette, Alain Viari, Tristan Stemmelen, Christine Carapito, Olivier Hermine, Richard Li, Daniel A. Lidar, Cécile Macquin, Jean Sibilia, Géraldine Laumond, Shweta Kailasan, Leslie Muller, Sabrina Bibi-Triki, Sylvie Schmidt, Aurélie Hirschler, Raony Guimaraes, Michael Simons, Anne Molitor, Francis Schneider, Damien Sanlaville, Thiên-Nga Chamaraux-Tran, Samira Fafi-Kremer, Pierre-Louis Tharaux, Thomas Chittenden, Angélique Pichot, A. Hanauer, Raphael Carapito, Mirjana Radosavljevic, Véronique Rolli, Bernard Goichot, Yvon Ruch, Olivier Collange, Ouria Tahar, Julien Pottecher, Khaldoun Kuteifan, Razieh Mohseninia, Perrine Spinnhirny, Alice Bernard, Bernard Drenou, Jean-Laurent Casanova, Elisa Pin, Jeffrey R. Gulcher, Paul-Michel Mertes, M. Javad Aman, Peter Nilsson, Jose Malagon-Lopez, François Danion, Yves Hansmann, Ferhat Meziani, Maleka Schenck, Nicodème Paul, Annabel Larnicol, Julia Frappier, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENOMAX [plateforme], Fédération Hospitalo-Universitaire OMICARE, Université de Strasbourg (UNISTRA), Nouvel Hôpital Civil de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Genuity Science [Boston], Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), University of Southern California (USC), Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpital de Hautepierre [Strasbourg], Yale School of Medicine [New Haven, Connecticut] (YSM), Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Groupe hospitalier de la région de Mulhouse et Sud-Alsace, Integrated biotherapeutics [Rockville], Royal Institute of Technology [Stockholm] (KTH ), Auragen [Lyon], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas, 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)-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), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Harvard Medical School [Boston] (HMS), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), CARAPITO, Christine, Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), LabEx Transplantex [Strasbourg], Fédération Hospitalo-Universitaire (OMICARE), Centre de Recherche d’Immunologie et d’Hématologie [Strasbourg], Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Département Ecologie, Physiologie et Ethologie (DEPE-IPHC), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Yale University School of Medicine, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Aucun, MEDLINE, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Artificial Intelligence, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, Humans, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, SARS-CoV-2, Confounding, COVID-19, Membrane Proteins, General Medicine, Respiration, Artificial, 3. Good health, ADAM Proteins, Intensive Care Units, 030220 oncology & carcinogenesis, Cohort, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Identification (biology), business
Abstract

International audience; The etiopathogenesis of critical COVID-19 remains unknown. Indeed given major confounding factors (age and comorbidities), true drivers of this condition have remained elusive. Here, we employ an unprecedented multi-omics analysis, combined with artificial intelligence, in a young patient cohort where major comorbidities have been excluded at the onset. Here, we established a three-tier cohort of individuals younger than 50 years without major comorbidities. These included 47 “critical” (in the ICU under mechanical ventilation) and 25 “non-critical” (in a non-critical care ward) COVID-19 patients as well as 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing and structural causal modeling led to key findings. Critical patients were characterized by exacerbated inflammation, perturbed lymphoid/myeloid compartments, coagulation and viral cell biology. Within a unique gene signature that differentiated critical from non-critical patients, several driver genes promoted critical COVID-19 among which the upregulated metalloprotease ADAM9 was key. This gene signature was supported in a second independent cohort of 81 critical and 73 recovered COVID-19 patients, as were ADAM9 transcripts, soluble form and proteolytic activity. Ex vivo ADAM9 inhibition affected SARS-CoV-2 uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, COVID-19 cohort, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. The key driver, ADAM9, interfered with SARS-CoV-2 biology. A repositioning strategy for anti-ADAM9 therapeutic is feasible.

Published
2021
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2. Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus host disease in conjunction with the CMV status

Author

Philippe Moreau, Machteld Oudshoorn, Catherine Paillard, Valérie Dubois, Raphael Carapito, Irina Kotova, Antoine Toubert, Ismail Aouadi, Perrine Spinnhirny, Eric Spierings, A. Parissiadis, Ibrahim Yakoub-Agha, Mauricette Michallet, Myriam Labalette, Seiamak Bahram, Régis Peffault de Latour, Jürgen Kuball, Mohamad Mohty, Christophe Picard, Bronno van der Holt, Didier Blaise, Ryad Tamouza, Myriam Maumy-Bertrand, Frédéric Bertrand, Pascale Loiseau, Véronique Rolli, Jan J. Cornelissen, Aurore Morlon, Anne Cesbron, Gérard Socié, Yasuo Morishima, Peter A. von dem Borne, Frans H.J. Claas, Cécile Macquin, Angélique Pichot, Bruno Lioure, Dominique Charron, Katia Gagne, Equipe Plate-forme GENOMAX (Inserm U1109), Fédération Hospitalo-Universitaire OMICARE-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA)-Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), INSERM Franco-Japanese Nextgen HLA Laboratory [Strasbourg] (FJ-HLA), Laboratoire International Associé (LIA), INSERM Franco-Japanese Nextgen HLA Laboratory[Nagano], Pôle de Biologie - Laboratoire d’Immunologie [Nouvel Hôpital Civil, Strasbourg] (Plateau Technique de Biologie), Nouvel Hôpital Civil - NHC [Strasbourg], BIOMICA SA [Strasbourg], Etablissement Français du Sang [Nantes], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Europdonor operated by Matchis Foundation [Leiden], Leiden University Medical Center (LUMC), Erasmus MC Cancer Institute, Rotterdam, Laboratoire d'Immunologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU 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), University Medical Center [Utrecht], Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Etablissement Français du Sang - Grand Est (EFS - alsace strasbourg), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de Recherche Mathématique Avancée (IRMA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Hôtel-Dieu [Paris], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre & marie Curie, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Aichi Cancer Center Research Institute, This work was supported by grants from the Agence Nationale de la Recherche (ANR) (ANR-11-LABX-0070_TRANSPLANTEX), and the INSERM (UMR_S 1109), the Institut Universitaire de France (IUF), all to SB, from the University of Strasbourg (IDEX UNISTRA) to CP and SB, from the European regional development fund (European Union) INTERREG V program (project n°3.2 TRIDIAG) to RC and SB, and from MSD-Avenir grant AUTOGEN to SB., We would like to thank Prof. Robert Zeiser (University of Freiburg/Germany) for critical reading of this manuscript. We thank Martin Verniquet for critical review of statistical analyses. We would also like to thank Nicole Raus (SFGM-TC, Lyon, France) for retrieving the clinical data from the ProMISe database., Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Hospitalo-Universitaire OMICARE-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universiteit Leiden, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hematology, Erasmus MC other, and Bernardo, Elizabeth

Subjects
medicine.medical_specialty, Congenital cytomegalovirus infection, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Typing, Amino Acids, Retrospective Studies, Transplantation, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, medicine.disease, 3. Good health, Graft-versus-host disease, 030220 oncology & carcinogenesis, Cytomegalovirus Infections, business, 030215 immunology
Abstract

International audience; Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.

Published
2020
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3. Zinc-Alpha-2-Glycoprotein in Inflammatory Bowel Disease

Author

Seiamak Bahram, Cécile Macquin, Laurent Peyrin-Biroulet, David Moulin, Véronique Rolli, Tunay Kökten, Ndeye-Coumba Ndiaye, Jean-Yves Jouzeau, Julie Hablot, Philippe Georgel, Patrick Netter, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunorhumathologie moléculaire, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, medicine.medical_specialty, Mice Knockout, [SDV]Life Sciences [q-bio], Zn-Alpha-2-Glycoprotein, Inflammatory bowel disease, Gastroenterology, Seminal Plasma Proteins/genetics, 03 medical and health sciences, Mice, Internal medicine, medicine, Immunology and Allergy, Animals, Humans, Colitis, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, business.industry, Animal, Zinc-Alpha-2-Glycoprotein, Case-control study, Seminal Plasma Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Seminal Plasma Proteins/blood, Disease Models, Animal, 030104 developmental biology, Ulcerative/blood, Case-Control Studies, Disease Models, Colitis, Ulcerative, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2018
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4. Lipolysis is altered in MHC class I zinc-alpha(2)-glycoprotein deficient mice

Author

Seiamak Bahram, Isabelle Castan-Laurell, V. Visentin, Valérie Astier, Véronique Rolli, Philippe Valet, Christian Carpéné, Mirjana Radosavljevic, Cécile Macquin, Susan Gilfillan, and Charlotte Guigné

Subjects
Male, Major histocompatibility complex, Gene Expression, Weight Gain, Zn-Alpha-2-Glycoprotein, Biochemistry, Mice, Structural Biology, Cricetinae, Adipocytes, Tissue Distribution, Mice, Knockout, biology, Gene targeting, Phenotype, Recombinant Proteins, HLA, Liver, Gene Targeting, medicine.medical_specialty, Lipolysis, Biophysics, Adrenergic beta-3 Receptor Agonists, Human leukocyte antigen, CHO Cells, In Vitro Techniques, Transfection, Immune system, Cricetulus, Internal medicine, MHC class I, Genetics, medicine, Animals, Humans, RNA, Messenger, Molecular Biology, Alleles, Base Sequence, Histocompatibility Antigens Class I, Seminal Plasma Proteins, Lipid metabolism, Cell Biology, DNA, Dietary Fats, Mice, Inbred C57BL, Endocrinology, Receptors, Adrenergic, beta-3, biology.protein, MHC, Non-classical MHC, HeLa Cells
Abstract

Non-conventional major histocompatibility complex class I molecules are involved in a variety of physiological functions, most at the periphery of the immune system per se. Zinc-alpha(2)-glycoprotein (ZAG), the sole soluble member of this superfamily has been implicated in cachexia, a poorly understood yet life-threatening, severe wasting syndrome. To further ascertain the role of ZAG in lipid metabolism and perhaps the immune system, we inactivated both ZAG alleles by gene targeting in mice. Subjecting these ZAG deficient animals to standard or lipid rich food regimens led to increased body weight in comparison to identically treated wild-type mice. This phenotype appeared to correlate with a significant decrease in adipocytic lipolysis that could not be rescued by several pharmacological agents including beta(3)-adrenoreceptor agonists. Furthermore, in contrast to previously reported data, ZAG was found to be ubiquitously and constitutively expressed, with an especially high level in the mouse liver. No overt immunological phenotype was identified in these animals.

Published
2006

5. B-domain deleted factor VIII is aggregated and degraded through proteasomal and lysosomal pathways

Author

Marie-Hélène Rodriguez, Cecile Ducasse, Nathalie Enjolras, Véronique Rolli, Benoît Guillet, Jean-Luc Plantier, and Claude Negrier

Subjects
Proteasome Endopeptidase Complex, Sucrose, Glycosylation, Leupeptins, Octoxynol, Detergents, Immunoblotting, Neuraminidase, CHO Cells, Biology, Transfection, chemistry.chemical_compound, Antigens, CD, hemic and lymphatic diseases, Lysosome, Cricetinae, Extracellular, medicine, Centrifugation, Density Gradient, Animals, Immunoprecipitation, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, Furin, Factor VIII, Microscopy, Confocal, Chinese hamster ovary cell, Tunicamycin, Leupeptin, Lysosome-Associated Membrane Glycoproteins, Hematology, Peptide Fragments, Protein Structure, Tertiary, medicine.anatomical_structure, chemistry, Biochemistry, Microscopy, Fluorescence, biology.protein, Lysosomes, Intracellular
Abstract

SummaryFactor VIII (FVIII) processing within mammalian cells is demonstrated to be much less efficient than proteins of similar size. The deletion of the B-domain from FVIII improves the level of production, due partly to the increase in mRNA synthesis. We aimed to characterise the cellular fate and the intracellular processing of the FVIII molecule devoid of B-domain. A B-domain deleted factor VIII (BDD-FVIII) possessing a furin consensus cleavage site in the connecting segment between the heavy and the light chain, was produced in CHO cell line. In such cells, FVIII was retained as two single chain products from which a majority was aggregated. The two species were located in Triton X-100 soluble (for 60–80%) and insoluble fractions (for 20–40%). The incubation of the expressing cells with tunicamycin (5 μg/ml) and the treatment of the intracellular species with a mixture of Neuraminidase and N-glycosidase-F revealed that both intracellular species were N-glycosylated. Furin over-expression neither diminished the intracellular FVIII contents nor improved its extracellular production. Intracellular FVIII was degraded through both lysosomal and proteasomal pathways as evidenced by inhibitor treatments (e.g. NH4Cl, leupeptin, clasto-Lactacystin β-lactone and MG-132), pulse-chase analysis and confocal observations. This study demonstrates that a BDD-FVIII expressed in CHO cells is inefficiently processed consecutively to intracellular aggregation, proteasomal degradation, and routage to lysosomes.

Published
2005

6. Generation of Factor VIII Molecules Partially Resistant to Activated Protein C

Author

Nathalie Enjolras, Véronique Rolli, Cecile Ducasse, Hans-Peter Hauser, Jean-Luc Plantier, Claude Negrier, Thomas Weimer, and Marie-Hélène Rodriguez

Subjects
Arginine, Chemistry, Immunology, Mutant, Wild type, Cell Biology, Hematology, medicine.disease, Biochemistry, Molecular biology, In vitro, Thrombin, In vivo, medicine, Activated protein C resistance, Protein C, medicine.drug
Abstract

Following a vascular injury, factor VIII (FVIII) is rapidly activated by thrombin cleavage at arginine (Arg) 372, 740 and 1689. Activated FVIII, an heterotrimer composed by the association of A1, A2 and A3-C1-C2 domains, is rapidly degraded to limit thrombosis risk. Two main phenomenons that account for the disappearence of FVIIIa consist of an intrinsic dissociation of the trimer due to the loss of A2 domain, and the cleavage of the molecule by activated protein C (APC). APC cleaves FVIIIa at Arg 336 and 562. Mutant FVIII molecules were already generated, with one or two arginines substituted, and a subsequent APC cleavage diminished. Since the thrombotic potential of high plasma levels of FVIII has been described, we aimed to generate new factor VIII molecules where the APC cleavage was only modulated. The ultimate goal being to increase in vivo the FVIIIa half-life. Among the two APC cleavage sites, the sequence around the site 562 was the most conserved between species. This region was therefore chosen to be modified with a prior verification that the amino-acids to be modified were not described in any hemophilic phenotype. Subsequently, the six following mutations were realized in a BDD-FVIII cDNA: Q561N, G563A, N564D, N564A, N564Q and I566M as well as the controls R336I, R562K and R336I+R562K. The constructs were transiently expressed in BHK cells to determine the specific activities of the corresponding molecules. The mutant specific activities, as determined by one- and two-stage clotting assays, ranged from 40 to 94 % of the wild-type except for G563A that was almost inactive. CHO clones expressing FVIII molecules were obtained. The mutants and control FVIII molecules were produced, partially purified on heparin column and further analyzed. The comparative specific activities in a two-stage clotting assay were the following (+/− SD; n=6): BDD-FVIII 100 %, Q561N 105 % +/− 45, G563A 6 % +/− 6, N564D 50 % +/− 23, N564A 45 % +/− 21, N564Q 80 % +/− 26, I566M 100 % +/− 41. The one-stage clotting assay gave identical results than the two-stage assay for each mutant. The mutants were then activated by thrombin (1:1) and the occurrence of FVIII activity was monitored. A 20- to 25-fold increase in FVIII activity was measured within 2 minutes following the addition of thrombin for all mutants. The mutants, except for the inactive G563A, were then analyzed for their resistance to APC by three different assays: an APC resistance kit (Coatest, Chromogenix), an in vitro assay that measured APC sensitivity of FVIIIa and an immunoblot assay that visualized the cleavage efficiency of the A2 fragment. These three assays confirmed the APC resistance of the previously published R336I, R562K and R336I+R562K, as compared with wild-type FVIII. They also revealed that the mutants N564D, N564A and I566M behaved similarly to the wild-type FVIII whereas Q561N and N564Q mutants were partially resistant to APC. The APC resistance ratio were the following 2.3 +/− 0.3 for BDD-FVIII, 2.1 +/− 0.4 for N564Q, 1.7 +/− 0,1 for Q561N, 1.6 +/− 0.3 for R562K and 1.3 +/− 0.3 for R336I+R562K. The N564Q and Q561N mutants exhibited a profile intermediate between wild type FVIII and R562K regarding of the loss of FVIIIa activity that was confirmed on the immunoblot profile. In conclusion we have generated new factor VIII molecules that retained their full procoagulant function while possessing a reduced sensitivity to APC cleavage.

Published
2004
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