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4. A condensate-hardening drug blocks RSV replication in vivo

Author

Risso-Ballester, Jennifer, Galloux, Marie, Cao, Jingjing, Le Goffic, Ronan, Hontonnou, Fortune, Jobart-Malfait, Aude, Desquesnes, Aurore, Sake, Svenja M., Haid, Sibylle, Du, Maiomiao, Zhang, Xiumei, Zhang, Huanyun, Wang, Zhaoguo, Rincheval, Vincent, Zhang, Youming, Pietschmann, Thomas, and Eleouet, Francois

Subjects
RNA, Biomolecules -- Usage -- Health aspects, Respiratory syncytial virus -- Control, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Biomolecular condensates have emerged as an important subcellular organizing principle.sup.1. Replication of many viruses, including human respiratory syncytial virus (RSV), occurs in virus-induced compartments called inclusion bodies (IBs) or viroplasm.sup.2,3. IBs of negative-strand RNA viruses were recently shown to be biomolecular condensates that form through phase separation.sup.4,5. Here we report that the steroidal alkaloid cyclopamine and its chemical analogue A3E inhibit RSV replication by disorganizing and hardening IB condensates. The actions of cyclopamine and A3E were blocked by a point mutation in the RSV transcription factor M2-1. IB disorganization occurred within minutes, which suggests that these molecules directly act on the liquid properties of the IBs. A3E and cyclopamine inhibit RSV in the lungs of infected mice and are condensate-targeting drug-like small molecules that have in vivo activity. Our data show that condensate-hardening drugs may enable the pharmacological modulation of not only many previously undruggable targets in viral replication but also transcription factors at cancer-driving super-enhancers.sup.6. Cyclopamine and its chemical analogue A3E inhibit replication of human respiratory syncytial virus (RSV) by hardening the liquid-liquid phase-separated inclusion bodies, resulting in the inhibition of virus replication in the lungs of RSV-infected mice., Author(s): Jennifer Risso-Ballester [sup.1] , Marie Galloux [sup.2] , Jingjing Cao [sup.3] , Ronan Le Goffic [sup.2] , Fortune Hontonnou [sup.2] , Aude Jobart-Malfait [sup.1] , Aurore Desquesnes [sup.1] , [...]

Published
2021
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5. Mucosal bivalent live attenuated vaccine protects against human metapneumovirus and respiratory syncytial virus in mice.

Author

Ogonczyk-Makowska, Daniela, Brun, Pauline, Vacher, Clémence, Chupin, Caroline, Droillard, Clément, Carbonneau, Julie, Laurent, Emilie, Dulière, Victoria, Traversier, Aurélien, Terrier, Olivier, Julien, Thomas, Galloux, Marie, Paul, Stéphane, Eléouët, Jean-François, Fouret, Julien, Hamelin, Marie-Eve, Pizzorno, Andrés, Boivin, Guy, Rosa-Calatrava, Manuel, and Dubois, Julia

Subjects
RESPIRATORY syncytial virus, LUNGS, MICE, ANTIBODY formation, RECOMBINANT viruses
Abstract

Live-Attenuated Vaccines (LAVs) stimulate robust mucosal and cellular responses and have the potential to protect against Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (HMPV), the main etiologic agents of viral bronchiolitis and pneumonia in children. We inserted the RSV-F gene into an HMPV-based LAV (Metavac®) we previously validated for the protection of mice against HMPV challenge, and rescued a replicative recombinant virus (Metavac®-RSV), exposing both RSV- and HMPV-F proteins at the virion surface and expressing them in reconstructed human airway epithelium models. When administered to BALB/c mice by the intranasal route, bivalent Metavac®-RSV demonstrated its capacity to replicate with reduced lung inflammatory score and to protect against both RSV and lethal HMPV challenges in vaccinated mice while inducing strong IgG and broad RSV and HMPV neutralizing antibody responses. Altogether, our results showed the versatility of the Metavac® platform and suggested that Metavac®-RSV is a promising mucosal bivalent LAV candidate to prevent pneumovirus-induced diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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6. A New Derivative of Retro-2 Displays Antiviral Activity against Respiratory Syncytial Virus

Author

Le Rouzic, Adrien, primary, Fix, Jenna, additional, Vinck, Robin, additional, Kappler-Gratias, Sandrine, additional, Volmer, Romain, additional, Gallardo, Franck, additional, Eléouët, Jean-François, additional, Keck, Mathilde, additional, Cintrat, Jean-Christophe, additional, Barbier, Julien, additional, Gillet, Daniel, additional, and Galloux, Marie, additional

Published
2023
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7. Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.

Author

Sake, Svenja M., Zhang, Xiaoyu, Rajak, Manoj Kumar, Urbanek-Quaing, Melanie, Carpentier, Arnaud, Gunesch, Antonia P., Grethe, Christina, Matthaei, Alina, Rückert, Jessica, Galloux, Marie, Larcher, Thibaut, Le Goffic, Ronan, Hontonnou, Fortune, Chatterjee, Arnab K., Johnson, Kristen, Morwood, Kaycie, Rox, Katharina, Elgaher, Walid A. M., Huang, Jiabin, and Wetzke, Martin

Subjects
CHIMERIC proteins, RESPIRATORY syncytial virus, VIRAL proteins, DRUG repositioning, HEPATITIS D virus
Abstract

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor. There is a need for effective antiviral drugs against RSV infection. Conducting an RSV repurposing screen using the ReFRAME library Sake et al. identify lonafarnib as an RSV fusion protein inhibitor, characterize its binding site within the viral protein and show its antiviral effects in a mouse model. [ABSTRACT FROM AUTHOR]

Published
2024
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8. A New Derivative of Retro-2 Displays Antiviral Activity against Respiratory Syncytial Virus.

Author

Le Rouzic, Adrien, Fix, Jenna, Vinck, Robin, Kappler-Gratias, Sandrine, Volmer, Romain, Gallardo, Franck, Eléouët, Jean-François, Keck, Mathilde, Cintrat, Jean-Christophe, Barbier, Julien, Gillet, Daniel, and Galloux, Marie

Subjects
RESPIRATORY syncytial virus, CELL culture, MEMBRANE glycoproteins, CELL membranes, RESPIRATORY infections, VIRAL transmission
Abstract

Human respiratory syncytial virus (hRSV) is the most common cause of bronchiolitis and pneumonia in newborns, with all children being infected before the age of two. Reinfections are very common throughout life and can cause severe respiratory infections in the elderly and immunocompromised adults. Although vaccines and preventive antibodies have recently been licensed for use in specific subpopulations of patients, there is still no therapeutic treatment commonly available for these infections. Here, we investigated the potential antiviral activity of Retro-2.2, a derivative of the cellular retrograde transport inhibitor Retro-2, against hRSV. We show that Retro-2.2 inhibits hRSV replication in cell culture and impairs the ability of hRSV to form syncytia. Our results suggest that Retro-2.2 treatment affects virus spread by disrupting the trafficking of the viral de novo synthetized F and G glycoproteins to the plasma membrane, leading to a defect in virion morphogenesis. Taken together, our data show that targeting intracellular transport may be an effective strategy against hRSV infection. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Hardening of Respiratory Syncytial Virus Inclusion Bodies by Cyclopamine Proceeds through Perturbation of the Interactions of the M2-1 Protein with RNA and the P Protein

Author

Diot, Cédric, primary, Richard, Charles-Adrien, additional, Risso-Ballester, Jennifer, additional, Martin, Davy, additional, Fix, Jenna, additional, Eléouët, Jean-François, additional, Sizun, Christina, additional, Rameix-Welti, Marie-Anne, additional, and Galloux, Marie, additional

Published
2023
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10. Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

Author

Cagno, Valeria, Andreozzi, Patrizia, D’Alicarnasso, Marco, Jacob Silva, Paulo, Mueller, Marie, Galloux, Marie, Le Goffic, Ronan, Jones, Samuel T., Vallino, Marta, Hodek, Jan, Weber, Jan, Sen, Soumyo, Janeček, Emma-Rose, Bekdemir, Ahmet, Sanavio, Barbara, Martinelli, Chiara, Donalisio, Manuela, Rameix Welti, Marie-Anne, Eleouet, Jean-Francois, Han, Yanxiao, Kaiser, Laurent, Vukovic, Lela, Tapparel, Caroline, Král, Petr, Krol, Silke, Lembo, David, and Stellacci, Francesco

Published
2018
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13. New Mucosal Bivalent Live-Attenuated Vaccine is Protective Against Human Metapneumovirus and Respiratory Syncytial Virus

Author

Ogonczyk-Makowska, Daniela, primary, Vacher, Clémence, additional, Pizzorno, Andrés, additional, Brun, Pauline, additional, Chupin, Caroline, additional, Droillard, Clément, additional, Carbonneau, Julie, additional, Laurent, Emilie, additional, Duliere, Victoria, additional, Traversier, Aurélien, additional, Terrier, Olivier, additional, Julien, Thomas, additional, Galloux, Marie, additional, Paul, Stephane, additional, Eleouet, Jean-Francois, additional, Hamelin, Marie-Ève, additional, Boivin, Guy, additional, Rosa-Calatrava, Manuel, additional, and Dubois, Julia, additional

Published
2023
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14. Investigation of the Fuzzy Complex between RSV Nucleoprotein and Phosphoprotein to Optimize an Inhibition Assay by Fluorescence Polarization

Author

Khodjoyan, Silva, primary, Morissette, Deborha, additional, Hontonnou, Fortune, additional, Checa Ruano, Luis, additional, Richard, Charles-Adrien, additional, Sperandio, Olivier, additional, Eléouët, Jean-François, additional, Galloux, Marie, additional, Durand, Philippe, additional, Deville-Foillard, Stéphanie, additional, and Sizun, Christina, additional

Published
2022
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15. Level of maternal antibodies against respiratory syncytial virus (RSV) nucleoprotein at birth and risk of RSV very severe lower respiratory tract infection

Author

Receveur, Matthieu, primary, Ottmann, Michèle, additional, Reynes, Jean‐Marc, additional, Eleouet, Jean‐François, additional, Galloux, Marie, additional, Receveur, Aurore, additional, Ploin, Dominique, additional, Fiorini, Sylvie, additional, Rivat, Nathalie, additional, Valette, Martine, additional, Lina, Bruno, additional, and Casalegno, Jean‐Sebastien, additional

Published
2022
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18. Les virus

Author

Biacchesi, Stéphane, primary, Chevalier, Christophe, additional, Galloux, Marie, additional, Langevin, Christelle, additional, Le Goffic, Ronan, additional, and Brémont, Michel, additional

Published
2017
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19. Macromolecular Viral Entry Inhibitors as Broad‐Spectrum First‐Line Antivirals with Activity against SARS‐CoV‐2

Author

Groß, Rüdiger, primary, Dias Loiola, Lívia Mesquita, additional, Issmail, Leila, additional, Uhlig, Nadja, additional, Eberlein, Valentina, additional, Conzelmann, Carina, additional, Olari, Lia‐Raluca, additional, Rauch, Lena, additional, Lawrenz, Jan, additional, Weil, Tatjana, additional, Müller, Janis A., additional, Cardoso, Mateus Borba, additional, Gilg, Andrea, additional, Larsson, Olivia, additional, Höglund, Urban, additional, Pålsson, Sandra Axberg, additional, Tvilum, Anna Selch, additional, Løvschall, Kaja Borup, additional, Kristensen, Maria M., additional, Spetz, Anna‐Lena, additional, Hontonnou, Fortune, additional, Galloux, Marie, additional, Grunwald, Thomas, additional, Zelikin, Alexander N., additional, and Münch, Jan, additional

Published
2022
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20. Investigation of the Fuzzy Complex between RSV Nucleoprotein and Phosphoprotein to Optimize an Inhibition Assay by Fluorescence Polarization.

Author

Khodjoyan, Silva, Morissette, Deborha, Hontonnou, Fortune, Checa Ruano, Luis, Richard, Charles-Adrien, Sperandio, Olivier, Eléouët, Jean-François, Galloux, Marie, Durand, Philippe, Deville-Foillard, Stéphanie, and Sizun, Christina

Subjects
NUCLEOPROTEINS, MOLECULAR interactions, C-terminal residues, NUCLEAR magnetic resonance, RESPIRATORY syncytial virus, FLUORESCENCE
Abstract

The interaction between Respiratory Syncytial Virus phosphoprotein P and nucleoprotein N is essential for the formation of the holo RSV polymerase that carries out replication. In vitro screening of antivirals targeting the N-P protein interaction requires a molecular interaction model, ideally consisting of a complex between N protein and a short peptide corresponding to the C-terminal tail of the P protein. However, the flexibility of C-terminal P peptides as well as their phosphorylation status play a role in binding and may bias the outcome of an inhibition assay. We therefore investigated binding affinities and dynamics of this interaction by testing two N protein constructs and P peptides of different lengths and composition, using nuclear magnetic resonance and fluorescence polarization (FP). We show that, although the last C-terminal Phe241 residue is the main determinant for anchoring P to N, only longer peptides afford sub-micromolar affinity, despite increasing mobility towards the N-terminus. We investigated competitive binding by peptides and small compounds, including molecules used as fluorescent labels in FP. Based on these results, we draw optimized parameters for a robust RSV N-P inhibition assay and validated this assay with the M76 molecule, which displays antiviral properties, for further screening of chemical libraries. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Level of maternal antibodies against respiratory syncytial virus (RSV) nucleoprotein at birth and risk of RSV very severe lower respiratory tract infection.

Author

Receveur, Matthieu, Ottmann, Michèle, Reynes, Jean‐Marc, Eleouet, Jean‐François, Galloux, Marie, Receveur, Aurore, Ploin, Dominique, Fiorini, Sylvie, Rivat, Nathalie, Valette, Martine, Lina, Bruno, and Casalegno, Jean‐Sebastien

Subjects
RESPIRATORY infections, RESPIRATORY syncytial virus, IMMUNOGLOBULINS, DELIVERY (Obstetrics), RESPIRATORY syncytial virus infection vaccines, PREMATURE infants
Abstract

Background: The nucleoprotein (N protein) of respiratory syncytial virus (RSV) is a candidate antigen for new RSV vaccine development. The aim of the present study was to investigate the association between maternal antibody titers against the RSV N protein at birth and the newborns' risk of developing very severe lower respiratory tract infection (VS‐LRTI). Methods: In this single‐center prospective cohort study, 578 infants born during the RSV epidemic season in France were included. Among these, 36 were hospitalized for RSV VS‐LRTI. A generalized linear model was used to test the occurrence of a VS‐LRTI in function of sex, mode of delivery, parity of the mother, type of pregnancy, date of birth in relation to the peak of the epidemic, and antibody titer against N protein. Results: All cord blood samples had detectable antibodies against N protein. The mean titers were significantly lower in newborns with risk factors for RSV severe LRTI (preterm infants, birth before the peak epidemic, multiparous mother). There was no association between antibody titer against the N protein and a protection against VS‐LRTI. Conclusions: Further studies are needed to support the hypothesis that transfer of maternal antibodies against the RSV N protein can provide a significant immune protection early in infancy and that N protein candidate vaccine may be a suitable target for maternal vaccine. [ABSTRACT FROM AUTHOR]

Published
2023
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26. Depletion of TAX1BP1 Amplifies Innate Immune Responses during Respiratory Syncytial Virus Infection

Author

Descamps, Delphyne, primary, Peres de Oliveira, Andressa, additional, Gonnin, Lorène, additional, Madrières, Sarah, additional, Fix, Jenna, additional, Drajac, Carole, additional, Marquant, Quentin, additional, Bouguyon, Edwige, additional, Pietralunga, Vincent, additional, Iha, Hidekatsu, additional, Morais Ventura, Armando, additional, Tangy, Frédéric, additional, Vidalain, Pierre-Olivier, additional, Eléouët, Jean-François, additional, and Galloux, Marie, additional

Published
2021
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27. Avian Cell Line DuckCelt®-T17 Is an Efficient Production System for Live-Attenuated Human Metapneumovirus Vaccine Candidate Metavac®

Author

Chupin, Caroline, primary, Pizzorno, Andrés, additional, Traversier, Aurélien, additional, Brun, Pauline, additional, Ogonczyk-Makowska, Daniela, additional, Padey, Blandine, additional, Milesi, Cédrine, additional, Dulière, Victoria, additional, Laurent, Emilie, additional, Julien, Thomas, additional, Galloux, Marie, additional, Lina, Bruno, additional, Eléouët, Jean-François, additional, Moreau, Karen, additional, Hamelin, Marie-Eve, additional, Terrier, Olivier, additional, Boivin, Guy, additional, Dubois, Julia, additional, and Rosa-Calatrava, Manuel, additional

Published
2021
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28. Author Correction: Mucosal bivalent live attenuated vaccine protects against human metapneumovirus and respiratory syncytial virus in mice.

Author

Ogonczyk-Makowska, Daniela, Brun, Pauline, Vacher, Clémence, Chupin, Caroline, Droillard, Clément, Carbonneau, Julie, Laurent, Emilie, Dulière, Victoria, Traversier, Aurélien, Terrier, Olivier, Julien, Thomas, Galloux, Marie, Paul, Stéphane, Eléouët, Jean-François, Fouret, Julien, Hamelin, Marie-Eve, Pizzorno, Andrés, Boivin, Guy, Rosa-Calatrava, Manuel, and Dubois, Julia

Subjects
RESPIRATORY syncytial virus, MICE, VACCINES
Abstract

This correction notice is related to an article published in the journal NPJ Vaccines. The correction states that the authors Guy Boivin, Manuel Rosa-Calatrava, and Julia Dubois should have been denoted as jointly supervising authors. The original article has been corrected accordingly. The authors of the article are listed as Daniela Ogonczyk-Makowska, Pauline Brun, Clémence Vacher, Caroline Chupin, Clément Droillard, Julie Carbonneau, Emilie Laurent, Victoria Dulière, Aurélien Traversier, Olivier Terrier, Thomas Julien, Marie Galloux, Stéphane Paul, Jean-François Eléouët, Julien Fouret, Marie-Eve Hamelin, Andrés Pizzorno, Guy Boivin, Manuel Rosa-Calatrava, and Julia Dubois. [Extracted from the article]

Published
2024
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29. A novel effective live-attenuated human metapneumovirus vaccine candidate produced in the serum-free suspension DuckCelt®-T17 cell platform

Author

Chupin, Caroline, primary, Pizzorno, Andrés, additional, Traversier, Aurélien, additional, Brun, Pauline, additional, Ogonczyk-Makowska, Daniela, additional, Padey, Blandine, additional, Milesi, Cédrine, additional, Dulière, Victoria, additional, Laurent, Emilie, additional, Julien, Thomas, additional, Galloux, Marie, additional, Lina, Bruno, additional, Eléouët, Jean-François, additional, Moreau, Karen, additional, Hamelin, Marie-Eve, additional, Terrier, Olivier, additional, Boivin, Guy, additional, Dubois, Julia, additional, and Rosa-Calatrava, Manuel, additional

Published
2021
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32. Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection

Author

Pålsson, Sandra Axberg, Dondalska, Aleksandra, Bergenstråhle, Joseph, Rolfes, Caroline, Björk, Albin, Sedano, Laura, Power, Ultan F., Rameix-Welti, Marie Anne, Lundeberg, Joakim L., Wahren-Herlenius, Marie, Mastrangelo, Peter, Eleouet, Jean François, Le Goffic, Ronan, Galloux, Marie, Spetz, Anna Lena, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Stockholm University, Royal Institute of Technology [Stockholm] (KTH ), Karolinska Institute, Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), School of Medicine, Dentistry and Biomedical Sciences [Belfast], Queen's University [Belfast] (QUB), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Laboratory Medicine and Pathobiology (LMP), University of Toronto, Vetenskapsrådet, VR: 521–2014–6718 Horizon 2020: 101003555, This work was supported by the Swedish Research Council https://www.vr.se/ (521–2014–6718) awarded to A-LS. This study was in part funded by the European Union's Horizon 2020 in response to the corona virus outbreak for research and innovation action under grant agreement No. 101003555., European Project: 101003555,H2020, RIA,H2020-SC1-PHE-CORONAVIRUS-2020,Fight-nCoV(2020), HAL UVSQ, Équipe, and FIGHTING-OFF CORONAVIRUS (SARS-CoV-2) WITH BROAD-SPECTRUM ANTIVIRALS: ESTABLISHING ANIMAL VIRAL CHALLENGE MODEL - Fight-nCoV - - H2020, RIA2020-04-01 - 2022-03-31 - 101003555 - VALID

Subjects
lcsh:Immunologic diseases. Allergy, ssON, viruses, Immunology, DNA, Single-Stranded, Respiratory Mucosa, Respiratory Syncytial Virus Infections, ISGs, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Mice, nucleolin, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Animals, Humans, respiratory syncytial virus (RSV), Chemokine CCL2, Original Research, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, oligonucleotides, RNA-Binding Proteins, single-stranded oligonucleotides, virus diseases, STAT2 Transcription Factor, Virus Internalization, respiratory system, Phosphoproteins, antiviral, Respiratory Syncytial Viruses, Chemokine CXCL10, STAT1 Transcription Factor, A549 Cells, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, Interferons, lcsh:RC581-607, Protein Binding
Abstract

International audience; Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Furthermore, we show that ssON’s antiviral activity was length dependent and that both RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON inhibited RSV infection by competing with the virus for binding to the cellular receptor nucleolin in vitro . Additionally, using a recombinant RSV that expresses luciferase we show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo resulted in the upregulation of RSV-induced interferon stimulated genes (ISGs) such as Stat1 , Stat2 , Cxcl10 , and Ccl2. This study highlights the possibility of using oligonucleotides as therapeutic agents against RSV infection. We demonstrate that the mechanism of action of ssON is the inhibition of viral entry in vitro , likely through the binding of the receptor, nucleolin and that ssON treatment against RSV infection in vivo additionally results in the upregulation of ISGs.

Published
2020

33. Single-Stranded Oligonucleotide-mediated Inhibition of Respiratory Syncytial Virus Infection

Author

Axberg Palsson, Sandra, Dondalska, Aleksandra, Bergenstrahle, Joseph A., Rolfes, Caroline, Bjork, Albin, Sedano, Laura, Power, Ultan, Remeix-Welti, Marie-Anne, Mastrangelo, Peter, Eleouet, Jean-Francois, Le Goffic, Ronan, Galloux, Marie, and Spetz, Anna-Lena

Subjects
SDG 3 - Good Health and Well-being, viruses, virus diseases, respiratory system
Abstract

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Furthermore, we show that ssON´s antiviral activity was length dependent and that both RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON inhibited RSV infection by competing with the virus for binding to the cellular receptor nucleolin in vitro. Additionally, using a recombinant RSV that expresses luciferase we show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo resulted in the upregulation of RSV-induced interferon stimulated genes (ISGs) such as Stat1, Stat2, Cxcl10 and Ccl2. This study highlights the possibility of using oligonucleotides as therapeutic agents against RSV infection. We demonstrate that the mechanism of action of ssON is the inhibition of viral entry in vitro, likely through the binding of the receptor, nucleolin and that ssON treatment against RSV infection in vivo additionallyresults in the upregulation of ISGs.

Published
2020

40. Targeting the Respiratory Syncytial Virus N 0 -P Complex with Constrained α-Helical Peptides in Cells and Mice

Author

Galloux, Marie, primary, Gsponer, Nadège, additional, Gaillard, Vanessa, additional, Fenner, Brice, additional, Larcher, Thibaut, additional, Vilotte, Marthe, additional, Rivière, Julie, additional, Richard, Charles-Adrien, additional, Eléouët, Jean-François, additional, Le Goffic, Ronan, additional, Mettier, Joelle, additional, and Nyanguile, Origène, additional

Published
2020
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41. De novo protein design enables the precise induction of RSV-neutralizing antibodies

Author

Sesterhenn, Fabian, primary, Yang, Che, additional, Bonet, Jaume, additional, Cramer, Johannes T., additional, Wen, Xiaolin, additional, Wang, Yimeng, additional, Chiang, Chi-I, additional, Abriata, Luciano A., additional, Kucharska, Iga, additional, Castoro, Giacomo, additional, Vollers, Sabrina S., additional, Galloux, Marie, additional, Dheilly, Elie, additional, Rosset, Stéphane, additional, Corthésy, Patricia, additional, Georgeon, Sandrine, additional, Villard, Mélanie, additional, Richard, Charles-Adrien, additional, Descamps, Delphyne, additional, Delgado, Teresa, additional, Oricchio, Elisa, additional, Rameix-Welti, Marie-Anne, additional, Más, Vicente, additional, Ervin, Sean, additional, Eléouët, Jean-François, additional, Riffault, Sabine, additional, Bates, John T., additional, Julien, Jean-Philippe, additional, Li, Yuxing, additional, Jardetzky, Theodore, additional, Krey, Thomas, additional, and Correia, Bruno E., additional

Published
2020
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42. Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry

Author

Blockus, Sebastian, primary, Sake, Svenja M., additional, Wetzke, Martin, additional, Grethe, Christina, additional, Graalmann, Theresa, additional, Pils, Marina, additional, Le Goffic, Ronan, additional, Galloux, Marie, additional, Prochnow, Hans, additional, Rox, Katharina, additional, Hüttel, Stephan, additional, Rupcic, Zeljka, additional, Wiegmann, Bettina, additional, Dijkman, Ronald, additional, Rameix-Welti, Marie-Anne, additional, Eléouët, Jean-François, additional, Duprex, W Paul, additional, Thiel, Volker, additional, Hansen, Gesine, additional, Brönstrup, Mark, additional, Haid, Sibylle, additional, and Pietschmann, Thomas, additional

Published
2020
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43. Respiratory syncytial virus tropism for olfactory sensory neurons in mice

Author

Bryche, Bertrand, primary, Frétaud, Maxence, additional, Saint‐Albin Deliot, Audrey, additional, Galloux, Marie, additional, Sedano, Laura, additional, Langevin, Christelle, additional, Descamps, Delphyne, additional, Rameix‐Welti, Marie‐Anne, additional, Eléouët, Jean‐François, additional, Le Goffic, Ronan, additional, and Meunier, Nicolas, additional

Published
2020
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44. Functional organization of cytoplasmic inclusion bodies in cells infected by respiratory syncytial virus

Author

Rincheval, Vincent, Lelek, Mickael, Gault, Elyanne, Bouillier, Camille, Sitterlin, Delphine, Blouquit-Laye, Sabine, Galloux, Marie, Zimmer, Christophe, Eleouet, Jean-François, Rameix-Welti, Marie-Anne, Infection et inflammation chronique (2I), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Hôpital Ambroise Paré, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), This study was supported by grants from the ANR (French national research agency), RESPISYNCYCELL project, from the Region Ile-de-France and by the 'Assistance Publique des Hôpitaux de Paris' (AP-HP). M.L and C.Z. acknowledge support from Institut Pasteur and Région Ile de France (DIM Malinf), We thank Dr Qin Yu from AstraZeneca R&D Boston—USA, for providing the AZ27 drug. We are grateful to Felix Rey, Jean-Louis Gaillard, Charles-Adrien Richard and Monica Bajorek for helpful discussions. Benoit Maury is gratefully acknowledged for technical assistance in microscopy experiments. We are grateful to the Cymages platform for access to SP8 Leica, which was supported by grants from the region Ile-de-France. We acknowledge Ignacio Izeddin for the gift of a mEos2 encoding plasmid. We acknowledge support from the INSERM and the Versailles Saint-Quentin University, ANR-13-ISV3-0007,RESPISYNCYCELL,Partenaires cellulaires du virus respiratoire syncytial(2013), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Ambroise Paré [AP-HP], Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Inclusion Bodies, transcription elongation-factor, nucleoprotein-rna complex, stress granules, m2-1 protein, crystal-structure, phase-separation, flash-palm, p-proteins, replication, cdna, Time-lapse imaging, Virus–host interactions, Science, viruses, DNA-Directed RNA Polymerases, Respiratory Syncytial Virus Infections, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Virus structures, Cytoplasmic Granules, Article, Cell Line, Viral Proteins, Nucleoproteins, Respiratory Syncytial Virus, Human, Humans, RNA, Viral, lcsh:Q, RNA, Messenger, Super-resolution microscopy, lcsh:Science
Abstract

Infection of cells by respiratory syncytial virus induces the formation of cytoplasmic inclusion bodies (IBs) where all the components of the viral RNA polymerase complex are concentrated. However, the exact organization and function of these IBs remain unclear. In this study, we use conventional and super-resolution imaging to dissect the internal structure of IBs. We observe that newly synthetized viral mRNA and the viral transcription anti-terminator M2-1 concentrate in IB sub-compartments, which we term “IB-associated granules” (IBAGs). In contrast, viral genomic RNA, the nucleoprotein, the L polymerase and its cofactor P are excluded from IBAGs. Live imaging reveals that IBAGs are highly dynamic structures. Our data show that IBs are the main site of viral RNA synthesis. They further suggest that shortly after synthesis in IBs, viral mRNAs and M2-1 transiently concentrate in IBAGs before reaching the cytosol and suggest a novel post-transcriptional function for M2-1., Respiratory syncytial virus (RSV) induces formation of inclusion bodies (IBs) sheltering viral RNA synthesis. Here, Rincheval et al. identify highly dynamic IB-associated granules (IBAGs) that accumulate newly synthetized viral mRNA and the viral M2-1 protein but exclude viral genomic RNA and RNA polymerase complexes.

Published
2017

45. Quand un virus pathogène détourne la machinerie cellulaire à son avantage

Author

Richard, Charles-Adrien, Rincheval, Vincent, Cardone, Christophe, Esneau, Camille, Galloux, Marie, Welti, Marie-Anne Rameix, Sizun, Christina, Eleouet, Jean Francois, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Unité de recherche Virologie et Immunologie Moléculaires (VIM), ICSN, Centre National de la Recherche Scientifique (CNRS), and ProdInra, Archive Ouverte

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Virus Respiratoire Syncytial, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Phosphorylation, Transcription
Abstract

Session "Dialogues agresseurs-hôtes, adaptations réciproques"; Le virus respiratoire syncytial (VRS) est le principal agent responsable de maladies respiratoires sévères (bronchiolites, pneumonies) chez l’Homme et le bovin. Le VRS est un virus enveloppé dont le génome est constitué d’un ARN simple brin de polarité négative, codant pour 11 protéines. Le génome est transcrit et répliqué par le complexe ARN polymérase viral. Composé de la nucléoprotéine N, de la polymérase L, de la phosphoprotéine P et du facteur de transcription M2-1, ce complexe ne possède pas toutes les fonctions enzymatiques nécessaires à son cycle viral. Par conséquent le virus doit exploiter la cellule pour se répliquer et se répandre dans les voies respiratoires. Ce détournement des fonctions cellulaires par les virus est toujours étonnant et surprenant par son ingéniosité, mais est difficile à démasquer.En cartographiant le site de P interagissant avec M2-1, de façon inattendue, nous avons observé qu’une mutation du résidu F87 situé en amont du site d’interaction avec M2-1 (région 90-110), empêchait la déphosphorylation de M2-1 sans effet sur l’interaction P-M2-1. De plus cette mutation a un effet drastique sur l’activité ARN polymérase. Ce résidu s’inscrit dans un motif de type « RVxF », impliqué dans la capture de la phosphatase-1 (PP1), protéine de la cellule hôte, par P. Par GST-pulldown et co-immunoprécipitation, nous avons montré que P interagit directement avec PP1 via ce domaine. De plus, par immunofluorescence et microscopie, nous avons observé que P recrute PP1 dans les centres réplicatifs viraux appelés « inclusion bodies » ou IBs. Enfin nous montrons que la surexpression de PP1 entraîne une accumulation de M2-1 déphosphorylée et diminue l’efficacité de la réplication du VRS. Nous en déduisons ainsi que le complexe P-PP1 régule la déphosphorylation de M2-1 et la transcription du VRS. En l'absence de PP1 des corps d'inclusion, M2-1 est exclue des granules associés aux IBs (IBAGs) formés par l'ARNm viral. Ces résultats suggèrent que M2-1 fonctionne non seulement en tant qu'antiterminateur de transcription, mais joue également un rôle critique post-transcriptionnel.

Published
2018

46. Driving immune responses with synthetic proteins - development of de novo designed immunogens to elicit respiratory syncytial virus neutralizing antibodies

Author

Sesterhenn, Fabian, Yang, Che, Bonet, Jaume, Galloux, Marie, Wen, Xiaolin, Cramer, Johannes Thomas, Henrioud, Patricia Corthesy, Rosset, Stéphane, Eleouet, Jean Francois, Jardetzky, Ted, Krey, Thomas, Riffault, Sabine, Correia, Bruno Emanuel, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Stanford University, Hannover Medical School [Hannover] (MHH), and Protein Society. USA. Beckman Coulter Inc, USA. Pall ForteBio, USA. Bristol-Myers Squibb (BMS), USA.

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

International audience

Published
2018

47. RSV hijacks cellular protein phosphatase 1 to regulate M2-1 phosphorylation and viral transcription

Author

Richard, Charles-Adrien, Rincheval, Vincent, Lassoued, Safa, fix, Jenna, Cardone, Christophe, Esneau, Camille, Nekhai, Sergei, Galloux, Marie, Rameix-Welti, Marie-Anne, Sizun, Christina, Eléouët, Jean Francois, Sizun, Christina, Eléouët, Jean Francois, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université Paris-Saclay, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Center for Sickle Cell Disease and Department of Medicine, Howard University, Laboratoire de Microbiologie, Centre Hospitalier Intercommunal Castres-Mazamet, ANR Blanc 2011 « Bronchioliteaser » [ANR-11-BSV8-0024], ANR Blanc 2013 « Respisyncycell » [ANR-13-ISV3-0007], NIH Research Grant U19AI109664, Region Ile-de-France DIM Malinf, CNRS IR-RMN-THC FR3050, Matthias Johannes Schnell, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Infection et inflammation chronique (2I), Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
0301 basic medicine, Transcription, Genetic, Virologie, Complexe polymérase, Sequence Homology, Biochemistry, Polymerases, Inclusion bodies, Facteur de transcription M2-1, Database and Informatics Methods, Transcription (biology), Protein Phosphatase 1, Phosphoprotéine P, Post-Translational Modification, Biology (General), Phosphorylation, Inclusion Bodies, Chemistry, Messenger RNA, DNA-Directed RNA Polymerases, Enzymes, 3. Good health, Cell biology, Nucleic acids, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, Oxidoreductases, Sequence Analysis, Luciferase, Research Article, Bioinformatics, QH301-705.5, Nucleic acid synthesis, DNA transcription, Immunology, Respiratory Syncytial Virus Infections, Protéine phosphatase 1 (PP1), Cytoplasmic Granules, Microbiology, Dephosphorylation, Transcription virale, Viral Proteins, 03 medical and health sciences, Sequence Motif Analysis, Virology, DNA-binding proteins, Genetics, Humans, Amino Acid Sequence, Chemical synthesis, RNA synthesis, Binding site, Transcription factor, Molecular Biology, Binding Sites, 030102 biochemistry & molecular biology, Virus Respiratoire Syncytial, Phosphatases, Biology and Life Sciences, Proteins, RNA, RC581-607, Research and analysis methods, Biosynthetic techniques, 030104 developmental biology, Respiratory Syncytial Virus, Human, Proteolysis, Enzymology, Parasitology, Gene expression, Immunologic diseases. Allergy
Abstract

Respiratory syncytial virus (RSV) RNA synthesis occurs in cytoplasmic inclusion bodies (IBs) in which all the components of the viral RNA polymerase are concentrated. In this work, we show that RSV P protein recruits the essential RSV transcription factor M2-1 to IBs independently of the phosphorylation state of M2-1. We also show that M2-1 dephosphorylation is achieved by a complex formed between P and the cellular phosphatase PP1. We identified the PP1 binding site of P, which is an RVxF-like motif located nearby and upstream of the M2-1 binding region. NMR confirmed both P-M2-1 and P-PP1 interaction regions in P. When the P–PP1 interaction was disrupted, M2-1 remained phosphorylated and viral transcription was impaired, showing that M2-1 dephosphorylation is required, in a cyclic manner, for efficient viral transcription. IBs contain substructures called inclusion bodies associated granules (IBAGs), where M2-1 and neo-synthesized viral mRNAs concentrate. Disruption of the P–PP1 interaction was correlated with M2-1 exclusion from IBAGs, indicating that only dephosphorylated M2-1 is competent for viral mRNA binding and hence for a previously proposed post-transcriptional function., Author summary Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness in infants. Since no vaccine and no potent antivirals are available against RSV, it is essential to better understand the mechanisms of viral replication to develop new antiviral strategies. Here we have investigated the mechanisms by which two essential components of the viral RNA polymerase machinery, the phosphoprotein P and the M2-1 transcription factor, interact and function. We identified the amino acid residues of P critical for this interaction and showed that they are required for P recruiting M2-1 to cytoplasmic inclusions, where viral polymerase complex proteins concentrate and viral RNA synthesis occurs. We also showed that M2-1 dephosphorylation, required for viral transcription, is achieved by a complex formed between P and the cellular phosphatase PP1. The region of P binding to PP1 is located nearby and upstream of the M2-1 binding domain. This is the first report showing that the phosphoprotein of a negative strand RNA virus can hijack a cellular phosphatase to modulate the phosphorylation state of its partners. These two P regions interacting with M2-1 and PP1 are also potential targets for future antiviral therapy.

Published
2018

48. De novo protein design enables precise induction of functional antibodies in vivo

Author

Sesterhenn, Fabian, primary, Yang, Che, additional, Bonet, Jaume, additional, Cramer, Johannes T, additional, Wen, Xiaolin, additional, Wang, Yimeng, additional, Chiang, Chi-I, additional, Abriata, Luciano A, additional, Kucharska, Iga, additional, Castoro, Giacomo, additional, Vollers, Sabrina S, additional, Galloux, Marie, additional, Dheilly, Elie, additional, Rosset, Stéphane, additional, Corthésy, Patricia, additional, Georgeon, Sandrine, additional, Villard, Mélanie, additional, Richard, Charles-Adrien, additional, Descamps, Delphyne, additional, Delgado, Teresa, additional, Oricchio, Elisa, additional, Rameix-Welti, Marie-Anne, additional, Más, Vicente, additional, Ervin, Sean, additional, Eléouët, Jean-François, additional, Riffault, Sabine, additional, Bates, John T, additional, Julien, Jean-Phillipe, additional, Li, Yuxing, additional, Jardetzky, Theodore, additional, Krey, Thomas, additional, and Correia, Bruno E, additional

Published
2019
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50. Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen

Author

Sesterhenn, Fabian, primary, Galloux, Marie, additional, Vollers, Sabrina S., additional, Csepregi, Lucia, additional, Yang, Che, additional, Descamps, Delphyne, additional, Bonet, Jaume, additional, Friedensohn, Simon, additional, Gainza, Pablo, additional, Corthésy, Patricia, additional, Chen, Man, additional, Rosset, Stéphane, additional, Rameix-Welti, Marie-Anne, additional, Éléouët, Jean-François, additional, Reddy, Sai T., additional, Graham, Barney S., additional, Riffault, Sabine, additional, and Correia, Bruno E., additional

Published
2019
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