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1. Polyclonal expansion of TCR Vb 21.3 + CD4 + and CD8 + T cells is a hallmark of multisystem inflammatory syndrome in children

Author

Olivier Dauwalder, David Klatzmann, Marie Duperril, Marion Moreews, Christine Lombard, Behrouz Kassai, Fanny Bajolle, Jean-Laurent Casanova, Anne-Laure Mathieu, Guillaume Monneret, Magali Perret, Rémi Pescarmona, Aurélie Portefaix, Jacqueline Marvel, Laurent Abel, Christophe Malcus, Tiphaine Louazon, Anne Moulin-Zinsch, Mehdi Mezidi, Lisa Giovannini-Chami, Omran Allatif, Hugues Patural, Thierry Walzer, Emilie Chopin, Francois Vandenesh, Encarnita Mariotti-Ferrandiz, Fabienne Venet, Céline Dupieux, Valérie Launay, Paul Bastard, Sophie Trouillet-Assant, Jean-Christophe Richard, Olivier Thaunat, Shen-Ying Zhang, Marine Villard, Samira Khaldi-Plassart, Kahina Saker, Alexandre Belot, Sophia Djebali, Marlène Dreux, Alicia Bellomo, Isabelle Rouvet, Robin Pouyau, Etienne Javouhey, Margaux Guerder, Sonia Teyssedre, Valérie Dubois, Kenz Le Gouge, Hugues Flodrops, Jean-Marie De Guillebon, 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), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hôpital Edouard Herriot [CHU - HCL], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de Reference des Staphylocoques, Université de Lyon, Centre hospitalier de Valence, Hôpital Louis Pradel [CHU - HCL], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), 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 de Paris (UP), Rockefeller University [New York], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hôpital de la Croix-Rousse [CHU - HCL], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), CHU Pitié-Salpêtrière [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)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-16-RHUS-0001,iMAP,iMAP(2016), Référent HAL, CIRI, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Immunology, T-cell receptor, Toxic shock syndrome, General Medicine, Human leukocyte antigen, Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Antigen, medicine, Cytotoxic T cell, 030212 general & internal medicine, Cytokine storm, CD8
Abstract

International audience; Multisystem inflammatory syndrome in children (MIS-C) is a delayed and severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease (KD) and toxic shock syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared with 16 KD, 58 TSS, and 42 coronavirus disease 2019 (COVID-19) cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFN-γ, sCD25, MCP1, and IL-1RA) in MIS-C, TSS, and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of patients with MIS-C and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3 + T cells from patients with MIS-C expressed high levels of HLA-DR, CD38, and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS, and acute COVID-19.

Published
2021
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2. HDV-Like Viruses

Author

Stéphanie Jacquet, Jimena Pérez-Vargas, Dominique Pontier, François-Loïc Cosset, Natalia Freitas, Rémi Pereira de Oliveira, Référent HAL, CIRI, IDEXLYON - - IDEXLYON2016 - ANR-16-IDEX-0005 - IDEX - VALID, Dynamiques eco-évolutives des maladies infectieuses - - ECOFECT2011 - ANR-11-LABX-0048 - LABX - VALID, PROJET AVENIR LYON SAINT-ETIENNE - - Avenir L.S.E.2011 - ANR-11-IDEX-0007 - IDEX - VALID, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), The laboratory of François-Loïc Cosset is supported by the Agence Nationale de la Recherche sur le SIDA et les Hépatites Virales | Maladies Infectieuses Emergentes (ANRS | MIE), the IDEXLYON (ANR-16-IDEX-0005) and the LabEx Ecofect (ANR-11-LABX-0048) of the 'Université de Lyon'(http://ecofect.universite-lyon.fr/, accessed on 25 April 2021), within the program 'Investissements d’Avenir' (ANR-11-IDEX-0007) operated by the ANR., ANR-16-IDEX-0005,IDEXLYON,IDEXLYON(2016), ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2011), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
Hepatitis C virus, viruses, [SDV]Life Sciences [q-bio], Review, Genome, Viral, Biology, medicine.disease_cause, Virus Replication, Microbiology, Virus, Host Specificity, Dengue fever, Evolution, Molecular, 03 medical and health sciences, Viral Proteins, Viral envelope, Virology, evolution, medicine, origin, Animals, Humans, helper virus, Phylogeny, 030304 developmental biology, Hepatitis B virus, 0303 health sciences, 030306 microbiology, virus diseases, biochemical phenomena, metabolism, and nutrition, medicine.disease, QR1-502, Hepatitis D, 3. Good health, HDV-like viruses, [SDV] Life Sciences [q-bio], Infectious Diseases, Novel virus, Helper virus, Human Virus, Hepatitis Delta Virus, Helper Viruses
Abstract

International audience; Hepatitis delta virus (HDV) is a defective human virus that lacks the ability to produce its own envelope proteins and is thus dependent on the presence of a helper virus, which provides its surface proteins to produce infectious particles. Hepatitis B virus (HBV) was so far thought to be the only helper virus described to be associated with HDV. However, recent studies showed that divergent HDV-like viruses could be detected in fishes, birds, amphibians, and invertebrates, without evidence of any HBV-like agent supporting infection. Another recent study demonstrated that HDV can be transmitted and propagated in experimental infections ex vivo and in vivo by different enveloped viruses unrelated to HBV, including hepatitis C virus (HCV) and flaviviruses such as Dengue and West Nile virus. All this new evidence, in addition to the identification of novel virus species within a large range of hosts in absence of HBV, suggests that deltaviruses may take advantage of a large spectrum of helper viruses and raises questions about HDV origins and evolution.

Published
2021
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3. A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity

Author

Legros, Vincent, Denolly, Solène, Vogrig, Manon, Boson, Bertrand, Siret, Eglantine, Rigaill, Josselin, Pillet, Sylvie, Grattard, Florence, Gonzalo, Sylvie, Verhoeven, Paul, Allatif, Omran, Berthelot, Philippe, Pélissier, Carole, Thiery, Guillaume, Botelho-Nevers, Elisabeth, Millet, Guillaume, Morel, Jérôme, Paul, Stéphane, Walzer, Thierry, Cosset, François-Loïc, Bourlet, Thomas, Pozzetto, Bruno, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), 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 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), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Physiopathologie et biothérapies des infections muqueuses (GIMAP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM), BioInformatique et BioStatistiques (BIBS), Référent HAL, CIRI, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet - Saint-Étienne (UJM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and ANR-21-COVR-0012,CORAR,Récupération des anosmies post COVID-19(2021)

Subjects
Adult, Male, viruses, Immunology, Pathogenesis, Antibodies, Viral, Severity of Illness Index, Article, COVID-19 Serological Testing, Prognostic markers, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Immunology and Allergy, Longitudinal Studies, Humoral response, skin and connective tissue diseases, Antibody, Aged, Aged, 80 and over, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, SARS-CoV-2, fungi, virus diseases, COVID-19, Middle Aged, Antibodies, Neutralizing, body regions, Kinetics, Infectious Diseases, Amino Acid Substitution, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Viral infection, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Spike Glycoprotein, Coronavirus, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female
Abstract

International audience; Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and, thus, for public health policy and vaccine development for COVID-19. In this study, using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein (Spike), we studied the neutralizing antibody (nAb) response in serum samples from a cohort of 140 SARS-CoV-2 qPCR-confirmed infections, including patients with mild symptoms and also more severe forms, including those that required intensive care. We show that nAb titers correlated strongly with disease severity and with anti-spike IgG levels. Indeed, patients from intensive care units exhibited high nAb titers; conversely, patients with milder disease symptoms had heterogeneous nAb titers, and asymptomatic or exclusive outpatient-care patients had no or low nAbs. We found that nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses. Moreover, we found an absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2, indicating that previous infection by human coronaviruses may not generate protective nAbs against SARS-CoV-2. Finally, we found that the D614G mutation in the spike protein, which has recently been identified as the current major variant in Europe, does not allow neutralization escape. Altogether, our results contribute to our understanding of the immune correlates of SARS-CoV-2-induced disease, and rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2 is warranted.

Published
2021
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4. Prognostic factors of severe community-acquired staphylococcal pneumonia in France

Author

Yves, Gillet, Anne, Tristan, Jean-Philippe, Rasigade, Mitra, Saadatian-Elahi, Coralie, Bouchiat, Michele, Bes, Oana, Dumitrescu, Marie, Leloire, Céline, Dupieux, Frédéric, Laurent, Gérard, Lina, Jerome, Etienne, Philippe, Vanhems, Laurent, Argaud, Francois, Vandenesch, Bruno, Soullie, Référent HAL, CIRI, Hospices Civils de Lyon (HCL), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Interdisciplinary Research and Innovation (CIRI), Aristotle University of Thessaloniki, Santé publique, épidémiologie et écologie évolutive des maladies infectieuses (PHE3ID), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.disease_cause, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Cohort Studies, 0302 clinical medicine, Community-acquired pneumonia, Leukocidins, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Pneumonia, Staphylococcal, 030212 general & internal medicine, Prospective Studies, Child, Aged, 80 and over, 0303 health sciences, Hazard ratio, Middle Aged, Prognosis, 3. Good health, Community-Acquired Infections, Staphylococcus aureus, Child, Preschool, Pleuropneumonia, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Panton Valentine leucocidin, France, Cohort study, Pulmonary and Respiratory Medicine, Adult, Methicillin-Resistant Staphylococcus aureus, medicine.medical_specialty, Adolescent, Exotoxins, Severity, 03 medical and health sciences, Young Adult, Intensive care, Internal medicine, Sepsis, medicine, Humans, Risk factor, Mortality, Aged, 030306 microbiology, business.industry, Infant, Newborn, Infant, biochemical phenomena, metabolism, and nutrition, medicine.disease, bacterial infections and mycoses, Pneumonia, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

PurposeStaphylococcus aureus causes severe forms of community-acquired pneumonia (CAP), namely staphylococcal pleuropneumonia in young children and staphylococcal necrotising pneumonia in older patients. Methicillin resistance and the Panton–Valentine leukocidin (PVL) toxin, as well as less specific factors, have been associated with poor outcome in severe CAP, but their roles are unclear.MethodsA prospective multicentre cohort study of severe staphylococcal CAP was conducted in 77 paediatric and adult intensive care units in France between January 2011 and December 2016. After age-clustering, risk factors for mortality, including pre-existing conditions, clinical presentation, laboratory features, strain genetic lineage, PVL, other virulence factors and methicillin resistance were assessed using univariate and multivariable Cox and LASSO (least absolute shrinkage and selection operator) regressions.ResultsOut of 163 included patients, aged 1 month to 87 years, 85 (52.1%) had PVL-positive CAP; there were 20 (12.3%) patients aged S. aureus lineages and the presence of other determinants of virulence.ConclusionPVL was associated with staphylococcal pleuropneumonia in toddlers and was a risk factor for mortality in older patients with severe CAP, independently of methicillin resistance, S. aureus genetic background and other virulence factors.

Published
2021

5. Toward Tightly Tuned Gene Expression Following Lentiviral Vector Transduction

Author

Page, Audrey, Fusil, Floriane, François-Loïc, Cosset, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), 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 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), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Référent HAL, CIRI, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
promoter, [SDV]Life Sciences [q-bio], Genetic Vectors, Lentivirus, transgene, Gene Transfer Techniques, lcsh:QR1-502, Gene Expression, lentiviral vectors, integration, Genetic Therapy, Review, Cellular Reprogramming, lcsh:Microbiology, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Transduction, Genetic, sensor, Animals, Humans, Transgenes, synthetic biology, Promoter Regions, Genetic, induction, signal
Abstract

International audience; Lentiviral vectors are versatile tools for gene delivery purposes. While in the earlier versions of retroviral vectors, transgene expression was controlled by the long terminal repeats (LTRs), the latter generations of vectors, including those derived from lentiviruses, incorporate internal constitutive or regulated promoters in order to regulate transgene expression. This allows to temporally and/or quantitatively control transgene expression, which is required for many applications such as for clinical applications, when transgene expression is required in specific tissues and at a specific timing. Here we review the main systems that have been developed for transgene regulated expression following lentiviral gene transfer. First, the induction of gene expression can be triggered either by external or by internal cues. Indeed, these regulated vector systems may harbor promoters inducible by exogenous stimuli, such as small molecules (e.g., antibiotics) or temperature variations, offering the possibility to tune rapidly transgene expression in case of adverse events. Second, expression can be indirectly adjusted by playing on inserted sequence copies, for instance by gene excision. Finally, synthetic networks can be developed to sense specific endogenous signals and trigger defined responses after information processing. Regulatable lentiviral vectors (LV)-mediated transgene expression systems have been widely used in basic research to uncover gene functions or to temporally reprogram cells. Clinical applications are also under development to induce therapeutic molecule secretion or to implement safety switches. Such regulatable approaches are currently focusing much attention and will benefit from the development of other technologies in order to launch autonomously controlled systems.

Published
2020
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6. HIV fusion: Catch me if you can

Author

Solène Denolly, François-Loïc Cosset, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Référent HAL, CIRI, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Electron Microscope Tomography, [SDV]Life Sciences [q-bio], Cell, Human immunodeficiency virus (HIV), Electrons, HIV Infections, medicine.disease_cause, Biochemistry, Membrane Fusion, Cell Line, 03 medical and health sciences, Viral envelope, medicine, Humans, Editors' Picks, Lipid bilayer, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Fusion, Membrane Glycoproteins, Total internal reflection fluorescence microscope, 030102 biochemistry & molecular biology, Chemistry, Vesicle, Cell Membrane, Cryoelectron Microscopy, env Gene Products, Human Immunodeficiency Virus, Virion, Membrane Proteins, Lipid bilayer fusion, Cell Biology, Cell biology, [SDV] Life Sciences [q-bio], HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, Microscopy, Fluorescence, Host-Pathogen Interactions, Editors' Picks Highlights, HIV-1, HeLa Cells
Abstract

To enter a cell and establish infection, HIV must first fuse its lipid envelope with the host cell plasma membrane. Whereas the process of HIV membrane fusion can be tracked by fluorescence microscopy, the 3D configuration of proteins and lipids at intermediate steps can only be resolved with cryo-electron tomography (cryoET). However, cryoET of whole cells is technically difficult. To overcome this problem, we have adapted giant plasma membrane vesicles (or blebs) from native cell membranes expressing appropriate receptors as targets for fusion with HIV envelope glycoprotein-expressing pseudovirus particles with and without Serinc host restriction factors. The fusion behavior of these particles was probed by TIRF microscopy on bleb-derived supported membranes. Timed snapshots of fusion of the same particles with blebs were examined by cryo-ET. The combination of these methods allowed us to characterize the structures of various intermediates on the fusion pathway and showed that when Serinc3 or Serinc5 (but not Serinc2) were present, later fusion products were more prevalent, suggesting that Serinc3/5 act at multiple steps to prevent progression to full fusion. In addition, the antifungal amphotericin B reversed Serinc restriction, presumably by intercalation into the fusing membranes. Our results provide a highly detailed view of Serinc restriction of HIV-cell membrane fusion and thus extend current structural and functional information on Serinc as a lipid-binding protein.

Published
2020
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7. Lentiviral Vector Pseudotypes: Precious Tools to Improve Gene Modification of Hematopoietic Cells for Research and Gene Therapy

Author

Alejandra Gutierrez-Guerrero, François-Loïc Cosset, Els Verhoeyen, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), 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 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), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Référent HAL, CIRI, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
T-Lymphocytes, viruses, [SDV]Life Sciences [q-bio], Genetic Vectors, lcsh:QR1-502, Review, HSC, lcsh:Microbiology, Vesicular stomatitis Indiana virus, Viral Envelope Proteins, Animals, Humans, NK cell, CRISPR/CAS9, pseudotyping, Gene Editing, B cell, Membrane Glycoproteins, Research, Lentivirus, lentiviral vector, Gene Transfer Techniques, Nipah Virus, T cell, Genetic Therapy, Hematopoietic Stem Cells, gene therapy, [SDV] Life Sciences [q-bio], Killer Cells, Natural, Measles virus, CRISPR-Cas Systems
Abstract

International audience; Viruses have been repurposed into tools for gene delivery by transforming them into viral vectors. The most frequently used vectors are lentiviral vectors (LVs), derived from the human immune deficiency virus allowing efficient gene transfer in mammalian cells. They represent one of the safest and most efficient treatments for monogenic diseases affecting the hematopoietic system. LVs are modified with different viral envelopes (pseudotyping) to alter and improve their tropism for different primary cell types. The vesicular stomatitis virus glycoprotein (VSV-G) is commonly used for pseudotyping as it enhances gene transfer into multiple hematopoietic cell types. However, VSV-G pseudotyped LVs are not able to confer efficient transduction in quiescent blood cells, such as hematopoietic stem cells (HSC), B and T cells. To solve this problem, VSV-G can be exchanged for other heterologous viral envelopes glycoproteins, such as those from the Measles virus, Baboon endogenous retrovirus, Cocal virus, Nipah virus or Sendai virus. Here, we provide an overview of how these LV pseudotypes improved transduction efficiency of HSC, B, T and natural killer (NK) cells, underlined by multiple in vitro and in vivo studies demonstrating how pseudotyped LVs deliver therapeutic genes or gene editing tools to treat different genetic diseases and efficiently generate CAR T cells for cancer treatment.

Published
2020
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8. HCV Interplay with Lipoproteins: Inside or Outside the Cells?

Author

François-Loïc, Cosset, Mialon, Chloé, Boson, Bertrand, Granier, Christelle, Denolly, Solène, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre 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 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), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Référent HAL, CIRI

Subjects
hepatitis C virus, Virus Assembly, [SDV]Life Sciences [q-bio], Virion, lcsh:QR1-502, immune escape, virus diseases, Review, Hepacivirus, Virus Internalization, Endoplasmic Reticulum, Lipid Metabolism, Hepatitis C, lcsh:Microbiology, [SDV] Life Sciences [q-bio], lipoproteins, Protein Transport, Host-Pathogen Interactions, Animals, Humans, lipidation, cell entry, Signal Transduction
Abstract

International audience; Hepatitis C virus (HCV) infection is a major public health issue leading to chronic liver diseases. HCV particles are unique owing to their particular lipid composition, namely the incorporation of neutral lipids and apolipoproteins. The mechanism of association between HCV virion components and these lipoproteins factors remains poorly understood as well as its impact in subsequent steps of the viral life cycle, such as entry into cells. It was proposed that the lipoprotein biogenesis pathway is involved in HCV morphogenesis; yet, recent evidence indicated that HCV particles can mature and evolve biochemically in the extracellular medium after egress. In addition, several viral, cellular and blood components have been shown to influence and regulate this specific association. Finally, this specific structure and composition of HCV particles was found to influence entry into cells as well as their stability and sensitivity to neutralizing antibodies. Due to its specific particle composition, studying the association of HCV particles with lipoproteins remains an important goal towards the rational design of a protective vaccine.

Published
2020
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9. An alternate conformation of HCV E2 neutralizing face as an additional vaccine target

Author

Yuanzi Hua, Rodrigo Velázquez-Moctezuma, Erick Giang, Fang Chen, Jannick Prentoe, Rameshwar U. Kadam, Steven K. H. Foung, Kenna Nagy, Mansun Law, Jens Bukh, Ian A. Wilson, Zhen-Yong Keck, Elias H. Augestad, Robyn L. Stanfield, Marlène Dreux, Netanel Tzarum, The Scripps Research Institute [La Jolla], University of California [San Diego] (UC San Diego), University of California-University of California, University of Copenhagen = Københavns Universitet (KU), Stanford University School of Medicine [CA, USA], 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), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, The Scripps Research Institute [La Jolla, San Diego], University of Copenhagen = Københavns Universitet (UCPH), 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), Référent HAL, CIRI, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
Viral Hepatitis Vaccines, Hepatitis C virus, [SDV]Life Sciences [q-bio], Hepacivirus, medicine.disease_cause, Neutralization, 03 medical and health sciences, Epitopes, 0302 clinical medicine, Viral entry, Structural Biology, Virology, medicine, Gene family, Humans, Receptor, Research Articles, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, biology, Hcv clearance, food and beverages, SciAdv r-articles, Hepatitis C Antibodies, Antibodies, Neutralizing, Hepatitis C, humanities, 3. Good health, [SDV] Life Sciences [q-bio], chemistry, biology.protein, 030211 gastroenterology & hepatology, Antibody, Glycoprotein, Research Article
Abstract

An alternate conformation is found for the major antibody target on hepatitis C virus to aid in rational vaccine design., To achieve global elimination of hepatitis C virus (HCV), an effective cross-genotype vaccine is needed. The HCV envelope glycoprotein E2 is the main target for neutralizing antibodies (nAbs), which aid in HCV clearance and protection. E2 is structurally flexible and functions in engaging host receptors. Many nAbs bind to the “neutralizing face” on E2, including several broadly nAbs encoded by the VH1-69 germline gene family that bind to a similar conformation (A) of this face. Here, a previously unknown conformation (B) of the neutralizing face is revealed in crystal structures of two of four additional E2–VH1-69 nAb complexes. In this conformation, the E2 front-layer region is displaced upon antibody binding, exposing residues in the back layer for direct antibody interaction. This E2 B structure may represent another conformational state in the viral entry process that is susceptible to antibody neutralization and thus provide a new target for rational vaccine development.

Published
2020
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10. Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

Author

Page, Audrey, Fusil, Floriane, Cosset, François-Loïc, Référent HAL, CIRI, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 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), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
[SDV] Life Sciences [q-bio], adoptive transfer, viral vectors, gene editing, antibody, [SDV]Life Sciences [q-bio], reprogramming, Review, cell engineering, neutralization, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, checkpoint inhibitors
Abstract

International audience; Cancers represent highly significant health issues and the options for their treatment are often not efficient to cure the disease. Immunotherapy strategies have been developed to modulate the patient’s immune system in order to eradicate cancerous cells. For instance, passive immunization consists in the administration at high doses of exogenously produced monoclonal antibodies directed either against tumor antigen or against immune checkpoint inhibitors. Its main advantage is that it provides immediate immunity, though during a relatively short period, which consequently requires frequent injections. To circumvent this limitation, several approaches, reviewed here, have emerged to induce in vivo antibody secretion at physiological doses. Gene delivery vectors, such as adenoviral vectors or adeno-associated vectors, have been designed to induce antibody secretion in vivo after in situ cell modification, and have driven significant improvements in several cancer models. However, anti-idiotypic antibodies and escape mutants have been detected, probably because of both the continuous expression of antibodies and their expression by unspecialized cell types. To overcome these hurdles, adoptive transfer of genetically modified B cells that secrete antibodies either constitutively or in a regulated manner have been developed by ex vivo transgene insertion with viral vectors. Recently, with the emergence of gene editing technologies, the endogenous B cell receptor loci of B cells have been modified with the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonuclease (Cas-9) system to change their specificity in order to target a given antigen. The expression of the modified BCR gene hence follows the endogenous regulation mechanisms, which may prevent or at least reduce side effects. Although these approaches seem promising for cancer treatments, major questions, such as the persistence and the re-activation potential of these engineered cells, remain to be addressed in clinically relevant animal models before translation to humans.

Published
2020
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11. Differential Roles of Lipin1 and Lipin2 in the Hepatitis C Virus Replication Cycle

Author

Pablo Gastaminza, Marlène Dreux, Gema Calvo, Ginés Ávila-Pérez, Victoria Castro, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Référent HAL, CIRI, Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 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), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
0301 basic medicine, hepatitis C virus, 0209 industrial biotechnology, Hepacivirus, 02 engineering and technology, Virus Replication, medicine.disease_cause, 01 natural sciences, 020901 industrial engineering & automation, Lipid homeostasis, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, lcsh:QH301-705.5, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Lipin, Nuclear Proteins, General Medicine, Hepatitis C, Cell biology, 3. Good health, Protein Transport, Gene Knockdown Techniques, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, symbols, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Hepatitis C virus, 030106 microbiology, Phosphatidate Phosphatase, Lipid signaling, RNA-dependent RNA polymerase, Context (language use), lcsh:A, Glycerophospholipids, Biology, Article, Cell Line, 03 medical and health sciences, symbols.namesake, medicine, Humans, Gene silencing, lipin, Diacylglycerol kinase, 010401 analytical chemistry, RNA, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Golgi apparatus, Lipid Metabolism, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 0104 chemical sciences, lipin family, lipid homeostasis, 030104 developmental biology, Viral replication, lcsh:Biology (General), lipid signaling, lcsh:General Works, hepatitis C
Abstract

© The Author(s)., Although their origin, nature and structure are not identical, a common feature of positive-strand RNA viruses is their ability to subvert host lipids and intracellular membranes to generate replication and assembly complexes. Recently, lipin1, a cellular enzyme that converts phosphatidic acid into diacylglycerol, has been implicated in the formation of the membranous web that hosts hepatitis C virus (HCV) replicase. In the liver, lipin1 cooperates with lipin2 to maintain glycerolipid homeostasis. We extended our previous study of the lipin family on HCV infection, by determining the impact of the lipin2 silencing on viral replication. Our data reveal that lipin2 silencing interferes with HCV virion secretion at late stages of the infection, without significantly affecting viral replication or assembly. Moreover, uninfected lipin2-, but not lipin1-deficient cells display alterations in mitochondrial and Golgi apparatus morphology, suggesting that lipin2 contributes to the maintenance of the overall organelle architecture. Finally, our data suggest a broader function of lipin2 for replication of HCV and other RNA viruses, in contrast with the specific impact of lipin1 silencing on HCV replication. Overall, this study reveals distinctive functions of lipin1 and lipin2 in cells of hepatic origin, a context in which they are often considered functionally redundant., This study was supported by grants SAF2014-52400-R and SAF2017-87846-R from Ministry of Science, Research and Universities from the Spanish Government (MCIU/AEI/FEDER, UE) and the International Program “Make Our Planet Great Again” (mopga-short-0000000612) from the French Government and European Union’s Horizon 2020 Research and innovation program under “ZIKALLIANCE” (Grant Agreement no. 734548) to MD. VC is supported by predoctoral fellowship BES-2015-074920 from MCIU/AEI/FEDER, UE.

Published
2019
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12. Characterization of Hepatitis C Virus Particle Subpopulations Reveals Multiple Usage of the Scavenger Receptor BI for Entry Steps

Author

Marlène Dreux, Ophélia Granio, Thomas F. Baumert, Ralf Bartenschlager, Maryse Guerin, Christelle Granier, François-Loïc Cosset, François Penin, Mirjam B. Zeisel, Viet Loan Dao Thi, Dimitri Lavillette, Jimmy Mancip, Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine II, University of Freiburg [Freiburg], Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Virology (DMV), Universität Heidelberg [Heidelberg], Plate-forme de R&D - Puces à Cellules Transfectées (PCT), Cancéropôle du Grand-Est (CGE)-Centre Européen de Biologie et de Génomique Structurale (CEBGS), Naiglin, Laurence, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Bases moléculaires et structurales des systèmes infectieux (BMSSI), Universität Heidelberg [Heidelberg] = Heidelberg University, Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Référent HAL, CIRI, Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
Apolipoprotein E, Very low-density lipoprotein, MESH: Virus Internalization, Hepacivirus, medicine.disease_cause, Biochemistry, MESH: Protein Structure, Tertiary, Mice, 0302 clinical medicine, Viral Envelope Proteins, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Animals, MESH: Hepacivirus, Receptor, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, chemistry.chemical_classification, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, virus diseases, Scavenger Receptors, Class B, MESH: Apolipoproteins E, 3. Good health, Cell biology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, lipids (amino acids, peptides, and proteins), 030211 gastroenterology & hepatology, MESH: Cell Line, Tumor, MESH: Rats, Viral protein, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Biology, Microbiology, Apolipoproteins E, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Scavenger receptor, MESH: Mice, Molecular Biology, 030304 developmental biology, MESH: Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, Virus Internalization, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Scavenger Receptors, Class B, digestive system diseases, Protein Structure, Tertiary, Rats, chemistry, MESH: Viral Envelope Proteins, Glycoprotein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Lipoprotein
Abstract

International audience; Hepatitis C virus (HCV) particles assemble along the very low density lipoprotein pathway and are released from hepatocytes as entities varying in their degree of lipid and apolipoprotein (apo) association as well as buoyant densities. Little is known about the cell entry pathway of these different HCV particle subpopulations, which likely occurs by regulated spatiotemporal processes involving several cell surface molecules. One of these molecules is the scavenger receptor BI (SR-BI), a receptor for high density lipoprotein that can bind to the HCV glycoprotein E2. By studying the entry properties of infectious virus subpopulations differing in their buoyant densities, we show that these HCV particles utilize SR-BI in a manifold manner. First, SR-BI mediates primary attachment of HCV particles of intermediate density to cells. These initial interactions involve apolipoproteins, such as apolipoprotein E, present on the surface of HCV particles, but not the E2 glycoprotein, suggesting that lipoprotein components in the virion act as host-derived ligands for important entry factors such as SR-BI. Second, we found that in contrast to this initial attachment, SR-BI mediates entry of HCV particles independent of their buoyant density. This function of SR-BI does not depend on E2/SR-BI interaction but relies on the lipid transfer activity of SR-BI, probably by facilitating entry steps along with other HCV entry co-factors. Finally, our results underscore a third function of SR-BI governed by specific residues in hypervariable region 1 of E2 leading to enhanced cell entry and depending on SR-BI ability to bind to E2.

Published
2012
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13. La susceptibilité à l’infection par le virus de l’hépatite C et la réponse antivirale sont modulées par le polymorphisme associé à l’interféron lambda

Author

Sonia Assil, Marlène Dreux, Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre 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 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), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Référent HAL, CIRI

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], General Medicine, Biology, Molecular biology, General Biochemistry, Genetics and Molecular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2014
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14. [Les exosomes sont porteurs d'ARN viral immunostimulant]

Author

Assil, Sonia, Décembre, Élodie, Dreux, Marlène, Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Référent HAL, 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 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), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2013
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15. Impact of the Autophagy Machinery on Hepatitis C Virus Infection

Author

Francis V. Chisari, Marlène Dreux, Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), 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 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), The Scripps Research Institute [La Jolla], University of California [San Diego] (UC San Diego), University of California-University of California, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Scripps Research Institute [La Jolla, San Diego], École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Référent HAL, CIRI

Subjects
hepatitis C virus, Autolysosome, lcsh:QR1-502, Review, Hepacivirus, medicine.disease_cause, Endoplasmic Reticulum, Virus Replication, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, lcsh:Microbiology, ER-stress response, RIG-I, 0302 clinical medicine, Interferon, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, unfolded protein response, interferon, Hepatitis C, autolysosome, 3. Good health, Cell biology, Infectious Diseases, 030220 oncology & carcinogenesis, Host-Pathogen Interactions, HCV, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, autophagic vesicle, RNA, Viral, Signal transduction, medicine.drug, Signal Transduction, Gene Expression Regulation, Viral, innate host response, autophagy, Hepatitis C virus, Biology, 03 medical and health sciences, Virology, medicine, Humans, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, Autophagy, Cell Membrane, Immunity, Innate, Viral replication, Unfolded protein response
Abstract

International audience; Autophagy is a cellular process that catabolizes cytoplasmic components and maintains energy homeostasis. As a stress response, the autophagy machinery interconnects a wide range of cellular pathways, enhancing the spread of certain pathogens while limiting others, and has become a highly active research area over the past several years. Independent laboratories have recently reported that autophagy vesicles accumulate in hepatitis C virus (HCV) infected cells and that autophagy proteins can function as proviral factors required for HCV replication. In this review, we summarize what is currently known about the interplay between autophagy and HCV and the possible mechanisms whereby autophagy proteins might favor HCV propagation.

Published
2011
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16. Structural basis of steroid hormone perception by the receptor kinase BRI1

Author

Tsegaye Dabi, Ian A. Wilson, Joseph P. Noel, Marlène Dreux, Michael Hothorn, Joanne Chory, Youssef Belkhadir, The Salk Institute for Biological Studies, Howard Hughes Medical Institute (HHMI), Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Scripps Research Institute [La Jolla, San Diego], 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 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), Scripps Research Institute, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Référent HAL, CIRI

Subjects
0106 biological sciences, Models, Molecular, medicine.medical_treatment, Molecular Sequence Data, Arabidopsis, Plasma protein binding, Biology, Crystallography, X-Ray, 01 natural sciences, Article, [SDV.BV.BOT] Life Sciences [q-bio]/Vegetal Biology/Botanics, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, Steroids, Heterocyclic, Plant Growth Regulators, Cell surface receptor, Brassinosteroids, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Brassinosteroid, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Binding site, Receptor, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Binding Sites, Superhelix, Arabidopsis Proteins, fungi, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, Protein Structure, Tertiary, Enzyme Activation, Steroid hormone, Structural biology, Biochemistry, chemistry, Protein Multimerization, Protein Kinases, Cholestanols, 010606 plant biology & botany, Protein Binding
Abstract

International audience; Polyhydroxylated steroids are regulators of body shape and size in higher organisms. In metazoans, intracellular receptors recognize these molecules. Plants, however, perceive steroids at membranes, using the membrane-integral receptor kinase BRASSINOSTEROID INSENSITIVE 1 (BRI1). Here we report the structure of the Arabidopsis thaliana BRI1 ligand-binding domain, determined by X-ray diffraction at 2.5 Å resolution. We find a superhelix of 25 twisted leucine-rich repeats (LRRs), an architecture that is strikingly different from the assembly of LRRs in animal Toll-like receptors. A 70-amino-acid island domain between LRRs 21 and 22 folds back into the interior of the superhelix to create a surface pocket for binding the plant hormone brassinolide. Known loss- and gain-of-function mutations map closely to the hormone-binding site. We propose that steroid binding to BRI1 generates a docking platform for a co-receptor that is required for receptor activation. Our findings provide insight into the activation mechanism of this highly expanded family of plant receptors that have essential roles in hormone, developmental and innate immunity signalling.

Published
2011
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17. Analysis of sulfobutyl ether-β-cyclodextrin mixtures by ion-spray mass spectrometry and liquid chromatography–ion-spray mass spectrometry

Author

Claire Elfakir, Sylvie Grard, Michel Dreux, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Référent HAL, CIRI, Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Electrospray, [SDV]Life Sciences [q-bio], Ion chromatography, Analytical chemistry, Ether, 02 engineering and technology, Mass spectrometry, 01 natural sciences, Biochemistry, Mass Spectrometry, Analytical Chemistry, chemistry.chemical_compound, Acetonitrile, ComputingMilieux_MISCELLANEOUS, Cyclodextrins, Chromatography, Chemistry, beta-Cyclodextrins, 010401 analytical chemistry, Organic Chemistry, General Medicine, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Solvent, [SDV] Life Sciences [q-bio], Mass spectrum, 0210 nano-technology, Ammonium acetate, Chromatography, Liquid
Abstract

The analysis of two commercial and two home-made sulfobutyl ether beta-cyclodextrin (SBE-beta-CD) samples by ion-spray (IS) mass spectrometry and by liquid chromatography-mass spectrometry coupling (LC-MS) is investigated in a negative ion mode. SBE-beta-CD fragmentation was first investigated by direct infusion. In IS, the best conditions for SBE-beta-CD ionization consisted of ammonium acetate added to an acetonitrile/water mixture as sample solvent. These conditions allowed simplification of the mass spectrum, mainly by the formation of dicharged species [M-2H]2-, thus limiting the production of multicharged fragments. IS-MS permits fast and simple measurement of the substitution pattern and determination of the global degree of substitution for SBE-beta-CD mixtures. A complementary method using LC-MS was developed for the analysis of these mixtures. The substitution patterns obtained by LC-MS are in good agreement with those determined by direct MS analysis. The LC-MS coupling enabled separation of the mixtures versus the charge in anion-exchange chromatography (AEC) whereas no separation of the different substitution isomers potentially present in the SBE-beta-CD mixture was displayed. The AEC methodology described can be successfully used for fractionation of SBE-beta-CD derivatives at the semi-preparative scale.

Published
2001
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18. Simultaneous analysis of underivatized chiral amino acids by liquid chromatography–ionspray tandem mass spectrometry using a teicoplanin chiral stationary phase

Author

Konstantinos Petritis, Alain Valleix, Claire Elfakir, Michel Dreux, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Référent HAL, CIRI

Subjects
Spectrometry, Mass, Electrospray Ionization, Stereochemistry, [SDV]Life Sciences [q-bio], 010402 general chemistry, Tandem mass spectrometry, 01 natural sciences, Biochemistry, High-performance liquid chromatography, Sensitivity and Specificity, Analytical Chemistry, medicine, Amino Acids, ComputingMilieux_MISCELLANEOUS, Detection limit, chemistry.chemical_classification, Aqueous solution, Chromatography, Chemistry, Teicoplanin, 010401 analytical chemistry, Organic Chemistry, Stereoisomerism, General Medicine, Orders of magnitude (mass), 0104 chemical sciences, Amino acid, [SDV] Life Sciences [q-bio], Enantiomer, medicine.drug, Chromatography, Liquid
Abstract

Simultaneous chiral separations of underivatized amino acids have been performed using a teicoplanin-based chiral stationary phase and ionspray tandem mass spectrometry for their ionisation and detection. Different amino acid enantiomer pairs were separated simultaneously, including those of positional isomeric amino acids (e.g., l , d -Leu/Ile, or l , d -Val/Iva). Due to the specificity of tandem mass spectrometry, co-eluting enantiomers of different amino acids could also be determined. Fifteen chiral underivatized proteinogenic and non-proteinogenic amino acids were analysed simultaneously under isocratic conditions (acetonitrile–water, 75:25) in less than 25 min. For maximum sensitivity, post-column addition of 500 mM aqueous HCOOH was necessary. Detection limits varied from 2.5 to 50 μg l−1 depending on the amino acid. The signal vs. concentration relationship was linear for all d - and l -amino acids (0.9995≤r2≤1) for three orders of magnitude.

Published
2001
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19. Determination at ppb level of an anti-human immunodeficiency virus nucleoside drug by capillary electrophoresis-electrospray ionization tandem mass spectrometry

Author

Hélène Dessans, Michel Dreux, Philippe Morin, Xavier Cahours, Luigi A. Agrofoglio, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Référent HAL, CIRI, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Detection limit, Electrospray, Spectrometry, Mass, Electrospray Ionization, Chromatography, 010405 organic chemistry, Chemistry, Anti-HIV Agents, Electrospray ionization, [SDV]Life Sciences [q-bio], 010401 analytical chemistry, Organic Chemistry, Electrophoresis, Capillary, Nucleosides, General Medicine, Mass spectrometry, Tandem mass spectrometry, 01 natural sciences, Biochemistry, 0104 chemical sciences, Analytical Chemistry, [SDV] Life Sciences [q-bio], Dideoxyadenosine, Capillary electrophoresis, Ionic strength, ComputingMilieux_MISCELLANEOUS
Abstract

Capillary electrophoresis coupled with tandem mass spectrometry was used to indirectly separate and quantify the active metabolite of the anti-human immunodeficiency virus (anti-HIV) didanosine drug. The influence of several parameters (pH and ionic strength of volatile formic acid-ammonia buffer) upon electroosmotic flow, electrophoretic mobility and peak efficiency of several nucleosides (A, dA, ddA, C) has been studied. This paper illustrates the current importance in CE-MS technique as a complementary or substituted method to the known HPLC-radioimmunoassay or HPLC-UV method to measure levels of anti-HIV drugs. The limit of detection for 2',3'-dideoxyadenosine by this method is 2 microg 1(-1) in a formic acid-ammonia buffer (pH 2.5, 10 mM ionic strength). This methodology could be used to perform simultaneous detection of two or more anti-HIV nucleosides, such as stavudine or didanosine in combination therapy.

Published
2000
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20. Parameter optimization for the analysis of underivatized protein amino acids by liquid chromatography and ionspray tandem mass spectrometry

Author

Konstantinos Petritis, Patrick Chaimbault, Michel Dreux, Claire Elfakir, Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Référent HAL, CIRI

Subjects
Electrospray, Spectrometry, Mass, Electrospray Ionization, [SDV]Life Sciences [q-bio], Analytical chemistry, 010402 general chemistry, Tandem mass spectrometry, Mass spectrometry, 01 natural sciences, Biochemistry, High-performance liquid chromatography, Analytical Chemistry, Amino Acids, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Chromatography, Chemistry, Elution, 010401 analytical chemistry, Organic Chemistry, Polyatomic ion, Proteins, General Medicine, 0104 chemical sciences, Amino acid, [SDV] Life Sciences [q-bio], Mass spectrum, Chromatography, Liquid
Abstract

The analysis of the 20 underivatized protein amino acids by liquid chromatography ionspray tandem mass spectrometry is investigated in positive ion mode. First, by direct infusion, amino acid fragmentation was investigated based on the product-ion mass spectrum of the parent compound in three different collision energies (10, 20, 30 eV). Then, the relative abundance of fragment ions was studied as a function of the collision energy in order to select the product ion with the highest abundance and to obtain the maximum sensitivity for each amino acid, by using the optimum collision energy. Depending on the amino acid, the loss of H 2 O or NH 3 or CH 2 O 2 was selected as the product ion from the molecular ion [M+H] + in selective reaction monitoring mode. 15 eV was chosen as a mean value of collision energy to obtain satisfactory sensitivity for the simultaneous determination of the 20 protein amino acids. In spite of the specificity of mass spectrometry, and in order to obtain maximum sensitivity, several pairs of amino acids had to be separated. The separation of these amino acids pairs was achieved in less than 20 min by using a porous graphitic carbon column and nonafluoropentanoic acid as ion-pairing reagent. Detection limits depending on the amino acid varied from 500 fmol to 40 pmol (using a 10 μl loop).

Published
2000
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