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

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

doi:10.3389/fimmu.2020.580547

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

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

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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 additionally
results in the upregulation of ISGs.

Original language	English
Article number	580547
Number of pages	12
Journal	Frontiers in Immunology
Volume	11
DOIs	https://doi.org/10.3389/fimmu.2020.580547
Publication status	Published - 08 Dec 2020

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Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection
Copyright 2020 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.05 MBLicence: CC BY

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Axberg Palsson, S., Dondalska, A., Bergenstrahle, J. A., Rolfes, C., Bjork, A., Sedano, L., Power, U., Remeix-Welti, M.-A., Mastrangelo, P., Eleouet, J.-F., Le Goffic, R., Galloux, M., & Spetz, A.-L. (2020). Single-Stranded Oligonucleotide-mediated Inhibition of Respiratory Syncytial Virus Infection. Frontiers in Immunology, 11, Article 580547. https://doi.org/10.3389/fimmu.2020.580547

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title = "Single-Stranded Oligonucleotide-mediated Inhibition of Respiratory Syncytial Virus Infection",

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.",

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AU - Axberg Palsson, Sandra

AU - Dondalska, Aleksandra

AU - Bergenstrahle, Joseph A.

AU - Rolfes, Caroline

AU - Bjork, Albin

AU - Sedano, Laura

AU - Power, Ultan

AU - Remeix-Welti, Marie-Anne

AU - Mastrangelo, Peter

AU - Eleouet, Jean-Francois

AU - Le Goffic, Ronan

AU - Galloux, Marie

AU - Spetz, Anna-Lena

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N2 - 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.

AB - 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.

U2 - 10.3389/fimmu.2020.580547

DO - 10.3389/fimmu.2020.580547

M3 - Article

SN - 1664-3224

VL - 11

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 580547

ER -

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

Abstract

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