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1. Potent human broadly SARS-CoV-2–neutralizing IgA and IgG antibodies effective against Omicron BA.1 and BA.2

Author

Planchais, Cyril, Fernández, Ignacio, Bruel, Timothée, de Melo, Guilherme, Prot, Matthieu, Beretta, Maxime, Guardado-Calvo, Pablo, Dufloo, Jérémy, Molinos-Albert, Luis, Backovic, Marija, Chiaravalli, Jeanne, Giraud, Emilie, Vesin, Benjamin, Conquet, Laurine, Grzelak, Ludivine, Planas, Delphine, Staropoli, Isabelle, Guivel-Benhassine, Florence, Hieu, Thierry, Boullé, Mikaël, Cervantes-Gonzalez, Minerva, Ungeheuer, Marie-Noëlle, Charneau, Pierre, van der Werf, Sylvie, Agou, Fabrice, Bartoli, Marie, Diallo, Alpha, Le Mestre, Soizic, Paul, Christelle, Petrov-Sanchez, Ventzislava, Yazdanpanah, Yazdan, Ficko, Cécile, Chirouze, Catherine, Andrejak, Claire, Malvy, Denis, Goehringer, François, Rossignol, Patrick, Gigante, Tristan, Gilg, Morgane, Rossignol, Bénédicte, Etienne, Manuel, Beluze, Marine, Bachelet, Delphine, Bhavsar, Krishna, Bouadma, Lila, Chair, Anissa, Charpentier, Charlotte, Chenard, Léo, Couffignal, Camille, Debray, Marie-Pierre, Descamps, Diane, Duval, Xavier, Eloy, Philippine, Esposito-Farese, Marina, Florence, Aline-Marie, Ghosn, Jade, Hoffmann, Isabelle, Kafif, Ouifiya, Khalil, Antoine, Lafhej, Nadhem, Laouénan, Cédric, Laribi, Samira, Le, Minh, Le Hingrat, Quentin, Letrou, Sophie, Mentré, France, Peytavin, Gilles, Piquard, Valentine, Roy, Carine, Schneider, Marion, Su, Richa, Tardivon, Coralie, Timsit, Jean-François, Tubiana, Sarah, Visseaux, Benoît, Deplanque, Dominique, Hulot, Jean-Sébastien, Diehl, Jean-Luc, Picone, Olivier, Angoulvant, François, Abrous, Amal, Couffin-Cadiergues, Sandrine, da Silva, Fernanda, Esperou, Hélène, Houas, Ikram, Jaafoura, Salma, Papadopoulos, Aurélie, Gaymard, Alexandre, Lina, Bruno, Rosa-Calatrava, Manuel, Dorival, Céline, Guedj, Jérémie, Lingas, Guillaume, Neant, Nadège, Abel, Laurent, Manda, Victoria, Behillil, Sylvie, Enouf, Vincent, Levy, Yves, Wiedemann, Aurélie, Arowas, Laurence, Perlaza, Blanca, Perrin de Facci, Louise, Chaouche, Sophie, Sangari, Linda, Renaudat, Charlotte, Fernandes Pellerin, Sandrine, van Platen, Cassandre, Jolly, Nathalie, Kuhmel, Lucie, Garaud, Valentine, Rafanoson, Hantaniaina, Gardais, Soazic, de Parseval, Nathalie, Dugast, Claire, Jannet, Caroline, Ropars, Sandrine, Momboisse, Fanny, Porteret, Isabelle, Cailleau, Isabelle, Hoen, Bruno, Tondeur, Laura, Besombes, Camille, Fontanet, Arnaud, Dimitrov, Jordan, Simon-Lorière, Etienne, Bourhy, Hervé, Montagutelli, Xavier, Rey, Félix, Schwartz, Olivier, Mouquet, Hugo, Covid Cohort Study Group, French, Study Group, Corser, Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris] (IP)-TheraVectys-Université Paris Cité (UPCité), Génétique de la souris - Mouse Genetics, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), FundingFunder(s): Institut PasteurFunder(s): French Government’s Investissements d’Avenir program Award Id(s): ANR-11-EQPX-0008Funder(s): Institut national de la santé et de la recherche médicaleFunder(s): REsearch & ACtion emergING infectious diseases (REACTing) consortiumFunder(s): Ministry of Health and Social AffairsFunder(s): Ministry of Higher Education and ResearchFunder(s): Agence Nationale de la Recherche Award Id(s): #20RR028-00Funder(s): European Commission Award Id(s): #101003589Funder(s): Fondation de France Award Id(s): #00106077Funder(s): Agence Nationale de Recherches sur le Sida et les Hépatites ViralesFunder(s): Programme hospitalier de recherche clinique Award Id(s): 20-0424, ANR-11-EQPX-0008,CACSICE,Centre d'analyse de systèmes complexes dans les environnements complexes(2011), ANR-21-CO14-0007,CoronaMito,Conséquences de l'infection par le SRAS-CoV-2 sur la fonction mitochondriale(2021), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Virologie Structurale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute (VRI), Processus infectieux à Trypanosomatidés - Trypanosomatids Infectious Processes, Institut Pasteur [Paris]-Université Paris Cité (UPCité), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Interactions Virus-Insectes - Insect-Virus Interactions (IVI), and Institut Pasteur [Paris]-TheraVectys-Université Paris Cité (UPCité)

Subjects
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, SARS-CoV-2, Immunoglobulin G, Spike Glycoprotein, Coronavirus, Immunology, Animals, COVID-19, Humans, Immunology and Allergy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Antibodies, Viral, Antibodies, Neutralizing, Immunoglobulin A
Abstract

International audience; Memory B-cell and antibody responses to the SARS-CoV-2 spike protein contribute to long-term immune protection against severe COVID-19, which can also be prevented by antibody-based interventions. Here, wide SARS-CoV-2 immunoprofiling in Wuhan COVID-19 convalescents combining serological, cellular, and monoclonal antibody explorations revealed humoral immunity coordination. Detailed characterization of a hundred SARS-CoV-2 spike memory B-cell monoclonal antibodies uncovered diversity in their repertoire and antiviral functions. The latter were influenced by the targeted spike region with strong Fc-dependent effectors to the S2 subunit and potent neutralizers to the receptor-binding domain. Amongst those, Cv2.1169 and Cv2.3194 antibodies cross-neutralized SARS-CoV-2 variants of concern, including Omicron BA.1 and BA.2. Cv2.1169, isolated from a mucosa-derived IgA memory B cell demonstrated potency boost as IgA dimers and therapeutic efficacy as IgG antibodies in animal models. Structural data provided mechanistic clues to Cv2.1169 potency and breadth. Thus, potent broadly neutralizing IgA antibodies elicited in mucosal tissues can stem SARS-CoV-2 infection, and Cv2.1169 and Cv2.3194 are prime candidates for COVID-19 prevention and treatment.

Published
2022
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2. Development of a highly specific and sensitive VHH-based sandwich immunoassay for the detection of the SARS-CoV-2 nucleoprotein

Author

Gransagne, Marion, Aymé, Gabriel, Brier, Sébastien, Chauveau-Le Friec, Gaëlle, Meriaux, Véronique, Nowakowski, Mireille, Déjardin, François, Levallois, Sylvain, Dias de Melo, Guilherme, Donati, Flora, Prot, Matthieu, Brûlé, Sébastien, Raynal, Bertrand, Bellalou, Jacques, Goncalves, Pedro, Montagutelli, Xavier, Di Santo, James, Lazarini, Françoise, England, Patrick, Petres, Stéphane, Escriou, Nicolas, Lafaye, Pierre, Département de Santé Globale - Department Global Health, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Plateforme Technologique de RMN Biologique et HDX-MS - Biological NMR and HDX-MS Technological Platform, Plateforme technologique Production et purification de protéines recombinantes – Production and Purification of Recombinant Proteins Technological Platform (PPR), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), Immunité Innée - Innate Immunity, Génétique de la souris - Mouse Genetics, Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), P. G. and J. P. D. received support from the ANR grant 'COVARIMM.'We want to thank Nicolas Wolff and Baptiste Colcombet-Cazenave for their technical help for the production of the different VHHs. The strain BetaCoV/France/IDF0372/2020 was supplied by the National Reference Centre for Respiratory Viruses hosted by Institut Pasteur (Paris, France) and headed by Pr. Sylvie van der Werf. The human sample from which strain BetaCoV/France/IDF0372/2020 was isolated was provided by Dr X. Lescure and Pr. Y. Yazdanpanah from the Bichat Hospital, Paris, France. Moreover, the strain BetaCoV/France/IDF0372/2020 was supplied through the European Virus Archive goes Global (Evag) platform, a project that has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 653316. We are grateful to the National Reference Center for Respiratory Viruses for providing the variants of concern used in mouse experiments, to Sylvie van der Werf and Etienne Simon-Lorière for support and scientific advice, and to Grégory Jouvion for histological evaluation. We thank the Institut Pasteur Histology platform for histological slides preparation. Mouse experiments on variants of concern were supported by ANR grants HUMOCID (ANR-20-COVI-0028-01) and IBEID (ANR-10-LABX-62-IBEID) and by the EU Horizon 2020 RECOVER project (No. 101003589). The authors would like to thank the DIM 1HEALTH région Ile-de-France scheme for funding the Centrifection project that allowed to purchase the Optima ultracentrifuge. The CACSICE Equipex ANR-11-EQPX-0008 is acknowledged., ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), ANR-20-COVI-0028,HuMoCID,Développement de modèles murins de COVID-19(2020), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-11-EQPX-0008,CACSICE,Centre d'analyse de systèmes complexes dans les environnements complexes(2011), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), Institut Pasteur [Paris], ENGLAND, Patrick, Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence - - CoVarImm2020 - ANR-20-COVI-0053 - COVID-19 - VALID, Développement de modèles murins de COVID-19 - - HuMoCID2020 - ANR-20-COVI-0028 - COVID-19 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Equipements d'excellence - Centre d'analyse de systèmes complexes dans les environnements complexes - - CACSICE2011 - ANR-11-EQPX-0008 - EQPX - VALID, European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID, and Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR)

Subjects
viruses, diagnostic, Enzyme-Linked Immunosorbent Assay, single domain antibodies, Limit of Detection, Cricetinae, Animals, Humans, NTD, N Terminal Domain of the Nucleoprotein, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, Research Articles, hydrogen‐deuterium exchange, nucleoprotein, antibody engineering, SARS-CoV-2, N, Nucleoprotein, CTD, C Terminal Domain of the Nucleoprotein, virus diseases, COVID-19, Covid19, Nucleocapsid Proteins, Single-Domain Antibodies, nanobodies, hydrogen-deuterium exchange, body regions, HDX-MS, Hydrogen Deuterium eXchange-Mass Spectrometry, immunochemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, Electrophoresis, Polyacrylamide Gel, phage display
Abstract

International audience; The current COVID-19 pandemic illustrates the importance of obtaining reliable methods for the rapid detection of SARS-CoV-2. A highly specific and sensitive diagnostic test able to differentiate the SARS-CoV-2 virus from common human coronaviruses is therefore needed. Coronavirus nucleoprotein (N) localizes to the cytoplasm and the nucleolus and is required for viral RNA synthesis. N is the most abundant coronavirus protein, so it is of utmost importance to develop specific antibodies for its detection. In this study, we developed a sandwich immunoassay to recognize the SARS-CoV-2 N protein. We immunized one alpaca with recombinant SARS-CoV-2 N and constructed a large single variable domain on heavy chain (VHH) antibody library. After phage display selection, seven VHHs recognizing the full N protein were identified by ELISA. These VHHs did not recognize the nucleoproteins of the four common human coronaviruses. Hydrogen Deuterium eXchange-Mass Spectrometry (HDX-MS) analysis also showed that these VHHs mainly targeted conformational epitopes in either the C-terminal or the N-terminal domains. All VHHs were able to recognize SARS-CoV-2 in infected cells or on infected hamster tissues. Moreover, the VHHs could detect the SARS variants B.1.17/alpha, B.1.351/beta, and P1/gamma. We propose that this sandwich immunoassay could be applied to specifically detect the SARS-CoV-2 N in human nasal swabs.

Published
2022
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3. SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance

Author

Robinot, Rémy, Hubert, Mathieu, de Melo, Guilherme Dias, Lazarini, Françoise, Bruel, Timothée, Smith, Nikaïa, Levallois, Sylvain, Larrous, Florence, Fernandes, Julien, Gellenoncourt, Stacy, Rigaud, Stéphane, Gorgette, Olivier, Thouvenot, Catherine, Trébeau, Céline, Mallet, Adeline, Duménil, Guillaume, Gobaa, Samy, Etournay, Raphaël, Lledo, Pierre-Marie, Lecuit, Marc, Bourhy, Hervé, Duffy, Darragh, Michel, Vincent, Schwartz, Olivier, Chakrabarti, Lisa, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris], Perception et Mémoire / Perception and Memory, Immunologie Translationnelle - Translational Immunology lab, Biologie des Infections - Biology of Infection, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Hub d'analyse d'images - Image Analysis Hub (Platform) (IAH), Institut de l'Audition [Paris] (IDA), Plateforme technologique Biomatériaux et Microfluidique - Biomaterials and Microfluidics technologic Platform, Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (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), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by: Institut Pasteur TASK FORCE SARS COV2 (TROPICORO project), the Urgence COVID-19 Fundraising Campaign of Institut Pasteur (COROCHIP project), DIM ELICIT Region Ile-de-France, and Agence Nationale de Recherche sur le SIDA et les Maladies Infectieuses Emergentes (ANRS, project 19052) (L.A.C.), the Vaccine Research Institute (ANR-10-LABX-77), ANRS, Labex IBEID (ANR-10-LABX-62-IBEID), the French National Research Agency (ANR, projects 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro-Immuno' ANR-14-CE14-0015-01), the Gilead HIV cure program, ANR/Fondation pour la Recherche Médicale (FRM) Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR (O.S.), Institut Pasteur TASK FORCE SARS COV2 and ANR Flash Covid CoVarImm (D.D.), Institut Pasteur TASK FORCE SARS COV2 (Neuro-Covid project) (H.B.). The Lledo lab is supported by the life insurance company 'AG2R-La-Mondiale'. The UtechS Photonic BioImaging (Imagopole) and the UtechS Ultrastructural BioImaging (UBI) are supported by the ANR (France BioImaging, ANR-10–INSB–04, Investments for the Future). R.R. is the recipient of a Sidaction fellowship, N.S. of a Pasteur-Roux-Cantarini fellowship, and St.G. of a MESR/Ecole Doctorale B3MI, Université de Paris fellowship. S.L. is supported by FRM (fellowship ECO201906009119) and by 'Ecole Doctorale FIRE—Programme Bettencourt'., We thank Florence Guivel-Benhassine for help with virus titration, Charlotte Calvet for help with sample preparation for scanning electron microscopy, Sylvie Van der Werf for the SARS-CoV-2 isolate used in this study, and Nicolas Escriou for the gift of a SARS-CoV-2 spike antibody., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-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), Vaccine Research Institute [Créteil, France] (VRI), Vougny, Marie-Christine, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Appel à projets générique - Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue - - TIMTAMDEN2014 - ANR-14-CE14-0029 - Appel à projets générique - VALID, and Appel à projets générique - Multiplication et Relation avec l'hôte du virus Chikungunya - - CHIKV-Viro-Immuno2014 - ANR-14-CE14-0015 - Appel à projets générique - VALID

Subjects
Male, Axoneme, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, viruses, MESH: Mesocricetus, MESH: Cricetinae, Respiratory Mucosa, MESH: Basal Bodies, Virus Replication, Article, MESH: Cilia, MESH: Forkhead Transcription Factors, Cricetinae, MESH: Respiratory Mucosa, Animals, Humans, MESH: COVID-19, MESH: Animals, MESH: SARS-CoV-2, MESH: Lung, Cilia, skin and connective tissue diseases, Lung, MESH: Cytokines, MESH: Humans, Mesocricetus, SARS-CoV-2, fungi, MESH: Virus Replication, COVID-19, Epithelial Cells, Forkhead Transcription Factors, respiratory system, MESH: Axoneme, Basal Bodies, MESH: Male, respiratory tract diseases, body regions, Mucociliary Clearance, MESH: Epithelial Cells, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Mucociliary Clearance
Abstract

Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. Here we examine the functional and structural consequences of SARS-CoV-2 infection in a reconstructed human bronchial epithelium model. SARS-CoV-2 replication causes a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remains limited. Rather, SARS-CoV-2 replication leads to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. Downregulation of the master regulator of ciliogenesis Foxj1 occurs prior to extensive cilia loss, implicating this transcription factor in the dedifferentiation of ciliated cells. Motile cilia function is compromised by SARS-CoV-2 infection, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramp up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrates the loss of motile cilia in vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma., SARS-CoV-2 infection damages the airways. Here the authors show that SARS-CoV-2 infection induces the rapid loss of airway motile cilia, resulting in altered cilia clearance function. Cilia loss is preceded by reduced expression of the ciliogenesis regulator Foxj1.

Published
2021
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4. Uppermost mantle velocity beneath the Mid-Atlantic Ridge and transform faults in the equatorial Atlantic Ocean

Author

Sampaio de Melo, Guilherme Weber, Parnell-Turner, Ross, Dziak, Robert, Smith, Deborah, Maia, Marcia, Royer, Jean-Yves, Universidade Federal do Rio Grande do Norte [Natal] (UFRN), Scripps Research Institute, NOAA Pacific Marine Environmental Laboratory [Newport] (PMEL), National Oceanic and Atmospheric Administration (NOAA), Woods Hole Oceanographic Institution (WHOI), Laboratoire Géosciences Océan (LGO), Institut Français de Recherche pour l'Exploitation de la Mer - Brest (IFREMER Centre de Bretagne), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS), Maia, Marcia, Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), and Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDU.STU.GP]Sciences of the Universe [physics]/Earth Sciences/Geophysics [physics.geo-ph], [SDU.STU.GP] Sciences of the Universe [physics]/Earth Sciences/Geophysics [physics.geo-ph], oceanic transform faults, seismology
Abstract

International audience; Seismic rays travelling just below the Moho provide insights into the thermal and compositional properties of the upper-mantle, and can be detected as Pn phases from regional earthquakes. Such phases are routinely identified in the continents, but in the oceans, detection of Pn phases is limited by a lack of long-term instrument deployments. We present estimates of upper-mantle velocity in the equatorial Atlantic Ocean from Pn arrivals beneath, and flanking, the Mid-Atlantic Ridge, and across several transform faults. We analyzed waveforms from 50 earthquakes with magnitude MW >3.5, recorded over 12 months in 2012-2013 by five autonomous hydrophones and a broadband seismograph located on the St. Peter and St. Paul archipelago. The resulting catalog of 152 ray paths allows us to resolve spatial variations in uppermantle velocities, which are consistent with estimates from nearby wide-angle seismic experiments. We find relatively high velocities near to the St. Paul transform system (~8.4 km s-1), compared to lower ridge-parallel velocities (~7.7 km s-1). Hence, this method is able to resolve ridge-transform scale velocity variations. Ray paths in lithosphere younger than 10 Myr have mean velocities of 7.9 ± 0.5 km s-1, which is slightly lower than those sampling lithosphere older than 20 Myr (8.1 km ± 0.3 s-1). There is no apparent systematic relationship between velocity and ray azimuth, which could be due to thickened lithosphere or complex mantle upwelling, although uncertainties in our velocity estimates may obscure such patterns. We also do not find any correlation between Pn velocity and shear wave speeds from the global SL2013sv model at depths < 150 km. Our results demonstrate that data from long-term deployments of autonomous hydrophones can be used to obtain rare and insightful estimates of uppermost mantle velocities over hundreds of kilometers, in otherwise inaccessible parts of the deep oceans.

Published
2020

5. Infections of the Central Nervous System - Chapter 13: Rabies

Author

de Melo, Guilherme Dias, Parize, Perrine, Jouvion, Grégory, Dacheux, Laurent, Chrétien, Fabrice, Bourhy, Hervé, Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris], Neuropathologie expérimentale / Experimental neuropathology, and Institut Pasteur [Paris]-Université de Paris (UP)

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

International audience

Published
2020
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6. Infections of the Central Nervous System - Chapter 13: Rabies

Author

de Melo, Guilherme Dias, Parize, Perrine, Jouvion, Grégory, Dacheux, Laurent, Chrétien, Fabrice, Bourhy, Hervé, Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris] (IP), Centre National de Référence de la Rage - National Reference Center Rabies (CNR), Centre collaborateur de l'OMS - Rage / World Health Organization Collaboration Centres - Rabies (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Service de Neuropathologie [Hôpital Sainte-Anne, Paris], Hôpital Sainte Anne, Fabrice Chrétien, Institut Pasteur [Paris], Institut Pasteur [Paris]-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Institut Pasteur [Paris]-Université de Paris (UP), and Université de Paris (UP)

Subjects
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Rabies is a preventable zoonotic disease caused by a neurotropic virus of the Lyssavirus genus. The virus is transmitted from animal to human by bites, scratches, or direct exposure of mucosal surfaces to infectious saliva. All mammals are susceptible to rabies, but only a few species (e.g. dogs and bats) are important reservoirs for the disease. The virus reaches the brain mainly by centripetal propagation mediated by retrograde transneuronal transfer. Once clinical signs appear, the disease almost invariably progresses to fatal encephalitis.

Published
2020
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7. New insights into experimental visceral leishmaniasis: Real-time in vivo imaging of Leishmania donovani virulence

Author

Melo, Guilherme D., Goyard, Sophie, Lecoeur, Hervé, Rouault, Eline, Pescher, Pascale, Fiette, Laurence, Boissonnas, Alexandre, Minoprio, Paola, Lang, Thierry, Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris], Processus infectieux à Trypanosomatidés - Trypanosomatids Infectious Processes, Institut Pasteur [Paris] (IP), Parasitologie moléculaire et Signalisation / Molecular Parasitology and Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Histopathologie humaine et Modèles animaux, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Dias de Melo, Guilherme

Subjects
Life Cycles, Leishmania Donovani, Luminescence, Physiology, Protozoology, Mice, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immune Physiology, Medicine and Health Sciences, Serial Passage, Luciferases, ComputingMilieux_MISCELLANEOUS, Mammals, Protozoans, Leishmania, Mice, Inbred BALB C, Virulence, Physics, Electromagnetic Radiation, lcsh:Public aspects of medicine, Eukaryota, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Liver, Vertebrates, Physical Sciences, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Hamsters, Leishmaniasis, Visceral, Protozoan Life Cycles, Bioluminescence, Anatomy, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Research Article, Amastigotes, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, Transfection, Microbiology, Rodents, Parasitic Diseases, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Mesocricetus, Promastigotes, Organisms, Biology and Life Sciences, lcsh:RA1-1270, Parasitic Protozoans, Disease Models, Animal, Amniotes, Luminescent Measurements, Spleen, Developmental Biology
Abstract

Visceral leishmaniasis is an insidious neglected disease with worldwide distribution. It is caused by parasites from the Leishmania donovani complex, which are able to be transmitted by different species of phlebotomine sand flies and to infect numerous mammal hosts. Despite the high number of people infected or at risk, and the remarkable quantity of studies focusing on this disease, a proper experimental model to efficiently decipher the infectious process of visceral leishmaniasis taking into account the nuances of parasite’s virulence and the duration of the infection is still lacking. Therefore, using golden Syrian hamsters and BALB/c mice, state-of-the-art genetic manipulation applied on a fully virulent L. donovani strain and in vivo imaging approaches, we describe herein three benefits for experimental visceral leishmaniasis: (i) the development of a double transfected bioluminescent (firefly luciferase) and fluorescent (E2-crimson) virulent strain of L. donovani (Ld1S_luci_E2-crimson), favoring a wide range of both in vivo and in vitro investigations, (ii) the establishment of a non-invasive mouse model to evaluate the infectious process during visceral leishmaniasis and the parasite’s virulence in real time, allowing longitudinal studies with the same animals, and (iii) the elaboration of a suitable method to reinstate (and verify anew) the virulence in a population of attenuated parasites, by recovering persistent parasites from chronic infected mice. Consequently, these results open up new perspectives on the study of visceral leishmaniasis, especially in the fields of therapeutics and vaccinology, since the model described herein renders now possible long-lasting follow up studies, with easy and accurate day-by-day verifications of the infection status along with a reduced number of laboratory animals. Trial registration ClinicalTrials.gov 2013-0047., Author summary Visceral leishmaniasis is a chronic disease caused by the life-threatening parasite Leishmania donovani. This chronicity character is a major concern in experimental models of visceral leishmaniasis, since infected animals do not develop any visible sign or symptom before one/two months after infection. Consequently, there is an urge to develop a model that allow the early identification of the parasite in the host’s tissues and an easy follow up of the infection. Therefore, we generated genetically-modified virulent parasites that are concomitantly fluorescent and bioluminescent, and using highly performant imaging approaches, we could detect these parasites in tissues of infected hamsters and mice within a week post-infection. With these parasites, we established, then, a mouse model of visceral leishmaniasis that allows prolonged longitudinal studies and enables the investigation of parasite’s survival, using non-invasive in vivo imaging techniques. These features are of extreme importance, particularly for the development of new therapies and vaccines and open up new perspectives on the study of this disease.

Published
2017
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