1. Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection
- Author
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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
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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
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