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Start Over Author "Barba-Spaeth, Giovanna" Topic antiviral agents
5 results on '"Barba-Spaeth, Giovanna"'

1. Defective viral genomes as therapeutic interfering particles against flavivirus infection in mammalian and mosquito hosts.

Author

Rezelj VV, Carrau L, Merwaiss F, Levi LI, Erazo D, Tran QD, Henrion-Lacritick A, Gausson V, Suzuki Y, Shengjuler D, Meyer B, Vallet T, Weger-Lucarelli J, Bernhauerová V, Titievsky A, Sharov V, Pietropaoli S, Diaz-Salinas MA, Legros V, Pardigon N, Barba-Spaeth G, Brodsky L, Saleh MC, and Vignuzzi M

Subjects
Aedes drug effects, Aedes virology, Animals, Chlorocebus aethiops, Computational Biology, Directed Molecular Evolution, Disease Models, Animal, Female, Genetic Fitness, Genome, Viral genetics, HEK293 Cells, Humans, Mice, Mosquito Control methods, Mosquito Vectors virology, Open Reading Frames genetics, RNA, Viral genetics, Vero Cells, Zika Virus Infection transmission, Zika Virus Infection virology, Antiviral Agents administration & dosage, Defective Viruses genetics, Mosquito Vectors drug effects, Zika Virus genetics, Zika Virus Infection drug therapy
Abstract

Arthropod-borne viruses pose a major threat to global public health. Thus, innovative strategies for their control and prevention are urgently needed. Here, we exploit the natural capacity of viruses to generate defective viral genomes (DVGs) to their detriment. While DVGs have been described for most viruses, identifying which, if any, can be used as therapeutic agents remains a challenge. We present a combined experimental evolution and computational approach to triage DVG sequence space and pinpoint the fittest deletions, using Zika virus as an arbovirus model. This approach identifies fit DVGs that optimally interfere with wild-type virus infection. We show that the most fit DVGs conserve the open reading frame to maintain the translation of the remaining non-structural proteins, a characteristic that is fundamental across the flavivirus genus. Finally, we demonstrate that the high fitness DVG is antiviral in vivo both in the mammalian host and the mosquito vector, reducing transmission in the latter by up to 90%. Our approach establishes the method to interrogate the DVG fitness landscape, and enables the systematic identification of DVGs that show promise as human therapeutics and vector control strategies to mitigate arbovirus transmission and disease.

Published
2021
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2. Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses.

Author

Mounce BC, Cesaro T, Moratorio G, Hooikaas PJ, Yakovleva A, Werneke SW, Smith EC, Poirier EZ, Simon-Loriere E, Prot M, Tamietti C, Vitry S, Volle R, Khou C, Frenkiel MP, Sakuntabhai A, Delpeyroux F, Pardigon N, Flamand M, Barba-Spaeth G, Lafon M, Denison MR, Albert ML, and Vignuzzi M

Subjects
Acetyltransferases metabolism, Animals, Cell Line, Chikungunya Fever drug therapy, Chikungunya Fever virology, Chikungunya virus drug effects, Chikungunya virus metabolism, Disease Outbreaks, Ebolavirus drug effects, Ebolavirus metabolism, Eflornithine pharmacology, Hemorrhagic Fever, Ebola drug therapy, Hemorrhagic Fever, Ebola virology, Humans, Mice, Mice, Inbred C57BL, Spermine analogs & derivatives, Spermine pharmacology, Virus Replication drug effects, Zika Virus drug effects, Zika Virus Infection drug therapy, Zika Virus Infection virology, Antiviral Agents pharmacology, Polyamines metabolism, RNA Viruses drug effects
Abstract

RNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise in vitro and in vivo, these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine N 1 -acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks, in vitro and in vivo These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO., Importance: RNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenues for targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facilitate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway for replication and highlights polyamine biosynthesis as a promising drug target., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Published
2016
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3. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.

Author

Marcello T, Grakoui A, Barba-Spaeth G, Machlin ES, Kotenko SV, MacDonald MR, and Rice CM

Subjects
Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular virology, Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Interferons, Liver Neoplasms pathology, Liver Neoplasms virology, Oligonucleotide Array Sequence Analysis, RNA, Viral genetics, Antiviral Agents pharmacology, Cytokines pharmacology, Gene Expression Regulation, Viral drug effects, Hepacivirus genetics, Interferon-alpha pharmacology, Interleukins pharmacology, Signal Transduction drug effects, Virus Replication drug effects
Abstract

Background & Aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Current therapy with pegylated interferon alpha (IFN-alpha) in combination with ribavirin is associated with adverse effects and often fails to induce a sustained response. IFN-lambdas, recently discovered IFN gene family members, exhibit antiviral and cell stimulatory activities similar to IFN-alpha. We aimed to determine whether IFN-lambda exhibits antiviral activity toward HCV and to compare the signal transduction and effector gene pathways with those of IFN-alpha., Methods: Using the HCV replicon system and cell culture infectious reporter virus, we compared IFN-alpha and IFN-lambda effects on HCV RNA replication and protein expression, as measured by quantitative reverse-transcriptase polymerase chain reaction, luciferase expression, and Western blot. Receptor expression and signaling pathways were explored using flow cytometry and Western blot. IFN-alpha- and IFN-lambda-mediated gene expression changes were compared using microarray analyses., Results: IFN-lambda exhibited dose- and time-dependent HCV inhibition, independent of types I and II IFN receptors. The kinetics of IFN-lambda-mediated signal transducers and activators of transcription (STAT) activation and induction of potential effector genes were distinct from those of IFN-alpha. IFN-lambda induced steady increases in levels of known interferon stimulated genes (ISGs), whereas IFN-alpha ISGs peaked early and declined rapidly. IFN-lambda inhibited replication of HCV genotypes 1 and 2 and enhanced the antiviral efficacy of subsaturating levels of IFN-alpha., Conclusions: These results demonstrate distinct differences in IFN-lambda- and IFN-alpha-induced antiviral states. Understanding these differences may prove useful for developing new HCV treatment strategies.

Published
2006
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4. Defective viral genomes as therapeutic interfering particles against flavivirus infection in mammalian and mosquito hosts

Author

Rezelj, Veronica V., Carrau, Lucía, Merwaiss, Fernando, Levi, Laura I., Erazo, Diana, Tran, Quang Dinh, Henrion-Lacritick, Annabelle, Gausson, Valérie, Suzuki, Yasutsugu, Shengjuler, Djoshkun, Meyer, Bjoern, Vallet, Thomas, Weger-Lucarelli, James, Bernhauerová, Veronika, Titievsky, Avi, Sharov, Vadim, Pietropaoli, Stefano, Diaz-Salinas, Marco A., Legros, Vincent, Pardigon, Nathalie, Barba-Spaeth, Giovanna, Brodsky, Leonid, Saleh, Maria-Carla, Vignuzzi, Marco, Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Virus et Interférence ARN - Viruses and RNA Interference, École Doctorale Bio Sorbonne Paris Cité [Paris] (ED BioSPC), Université Sorbonne Paris Cité (USPC)-Université de Paris (UP), University of Haifa [Haifa], Virologie Structurale - Structural Virology, Environnement et Risques infectieux - Environment and Infectious Risks (ERI), Institut Pasteur [Paris], This work was funded by the DARPA INTERCEPT program managed by Dr. Jim Gimlett, Dr. Brad Ringiesen, and Dr. Seth Cohen and administered through DARPA Cooperative Agreement #HR0011-17-2-0023 (the content of the information does not necessarily reflect the position or the policy of the U.S. government, and no official endorsement should be inferred). This work also received funding from the Fondation de recherche médicale, FRM EQU201903007777, and the Agence Nationale de Recherche Laboratoire d’Excellence grant ANR-10-LABX-62-IBEID., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)

Subjects
Mosquito Control, viruses, [SDV]Life Sciences [q-bio], Mice, MESH: Genetic Fitness, Aedes, MESH: Chlorocebus aethiops, Chlorocebus aethiops, MESH: Directed Molecular Evolution, MESH: Animals, MESH: Mosquito Control, Zika Virus Infection, Defective Viruses, MESH: Defective Viruses, MESH: Aedes, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: HEK293 Cells, MESH: RNA, Viral, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, Female, MESH: Mosquito Vectors, MESH: Genome, Viral, MESH: Computational Biology, MESH: Antiviral Agents, Science, MESH: Vero Cells, MESH: Zika Virus, Genome, Viral, Mosquito Vectors, Antiviral Agents, Article, Open Reading Frames, MESH: Zika Virus Infection, Virology, Animals, Humans, Vero Cells, MESH: Mice, MESH: Humans, Computational Biology, Zika Virus, MESH: Open Reading Frames, Disease Models, Animal, HEK293 Cells, Viral infection, Genetic Fitness, Directed Molecular Evolution, MESH: Disease Models, Animal, MESH: Female
Abstract

Arthropod-borne viruses pose a major threat to global public health. Thus, innovative strategies for their control and prevention are urgently needed. Here, we exploit the natural capacity of viruses to generate defective viral genomes (DVGs) to their detriment. While DVGs have been described for most viruses, identifying which, if any, can be used as therapeutic agents remains a challenge. We present a combined experimental evolution and computational approach to triage DVG sequence space and pinpoint the fittest deletions, using Zika virus as an arbovirus model. This approach identifies fit DVGs that optimally interfere with wild-type virus infection. We show that the most fit DVGs conserve the open reading frame to maintain the translation of the remaining non-structural proteins, a characteristic that is fundamental across the flavivirus genus. Finally, we demonstrate that the high fitness DVG is antiviral in vivo both in the mammalian host and the mosquito vector, reducing transmission in the latter by up to 90%. Our approach establishes the method to interrogate the DVG fitness landscape, and enables the systematic identification of DVGs that show promise as human therapeutics and vector control strategies to mitigate arbovirus transmission and disease., Defective viral genomes (DVGs) can interfere with virus replication and provide a potential approach to control infection. Here, Rezelj et al. use a combined experimental evolution and computational approach to identify DVG sequences that optimally interfere with Zika virus infection and show antiviral activity in mice and mosquitoes.

Published
2021

5. Sensitive visualization of SARS-CoV-2 RNA with CoronaFISH

Author

Elena Rensen, Stefano Pietropaoli, Florian Mueller, Christian Weber, Sylvie Souquere, Sina Sommer, Pierre Isnard, Marion Rabant, Jean-Baptiste Gibier, Fabiola Terzi, Etienne Simon-Loriere, Marie-Anne Rameix-Welti, Gérard Pierron, Giovanna Barba-Spaeth, Christophe Zimmer, Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), National Cystic Fibrosis Reference Center [CHU Necker] (CNR - INSERM U1151), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), 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], Institut Gustave Roussy (IGR), Virologie Structurale - Structural Virology, E Simon-Loriere acknowledges funding from the French Government’s Investissement d’Avenir program, 'INCEPTION’ (ANR-16-CONV-0005). G Barba-Spaeth acknowledges funding by the Institut Pasteur Coronavirus task force (don AXA COVID-19 project COVID-SPREAD). C Zimmer acknowledges funding by Fondation pour la Recherche Médicale (Equipe FRM, DEQ 20150331762), Institut Carnot Pasteur MS, and Institut Pasteur., We would like to thank Edouard Bertrand, who originally developed smiFISH and Hans Johansson for insightful discussions. We also thank Guillaume Dumenil (Ultrastructural Bioimaging UTechS of Institut Pasteur) for having suggested the application of CoronaFISH to EM and for follow-up discussions. We thank Nathalie Jolly and Nathalie Clément (Center for Translational Science, Institut Pasteur) and Cloé Giquel (Legal department, Institut Pasteur) for their help in obtaining authorization to use patient samples., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Barba Spaeth, Giovanna, Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), Département Croissance et Signalisation [Paris], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
[SDV]Life Sciences [q-bio], viruses, Health, Toxicology and Mutagenesis, Plant Science, Virus Replication, Antiviral Agents, Sensitivity and Specificity, Biochemistry, Genetics and Molecular Biology (miscellaneous), 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Chlorocebus aethiops, Animals, Humans, Vero Cells, In Situ Hybridization, In Situ Hybridization, Fluorescence, Virus Release, Research Articles, 030304 developmental biology, 0303 health sciences, Alanine, Ecology, SARS-CoV-2, COVID-19, Reproducibility of Results, respiratory system, Adenosine Monophosphate, respiratory tract diseases, COVID-19 Drug Treatment, 3. Good health, [SDV] Life Sciences [q-bio], Microscopy, Electron, RNA, Viral, Caco-2 Cells, 030217 neurology & neurosurgery, Research Article
Abstract

We design an RNA-FISH method to target the plus and minus strands of SARS-CoV-2 RNA, and apply it to image the virus in cell lines, lung tissue, and nasal swabs, by fluorescence and electron microscopy., The current COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The positive-sense single-stranded RNA virus contains a single linear RNA segment that serves as a template for transcription and replication, leading to the synthesis of positive and negative-stranded viral RNA (vRNA) in infected cells. Tools to visualize vRNA directly in infected cells are critical to analyze the viral replication cycle, screen for therapeutic molecules, or study infections in human tissue. Here, we report the design, validation, and initial application of FISH probes to visualize positive or negative RNA of SARS-CoV-2 (CoronaFISH). We demonstrate sensitive visualization of vRNA in African green monkey and several human cell lines, in patient samples and human tissue. We further demonstrate the adaptation of CoronaFISH probes to electron microscopy. We provide all required oligonucleotide sequences, source code to design the probes, and a detailed protocol. We hope that CoronaFISH will complement existing techniques for research on SARS-CoV-2 biology and COVID-19 pathophysiology, drug screening, and diagnostics.

Published
2022

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