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Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α

Varicella-zoster virus (VZV) infection of neuronal cells and the activation of cell-intrinsic antiviral responses upon infection are still poorly understood mainly due to the scarcity of suitable human in vitro models that are available to study VZV. We developed a compartmentalized human-induced pl...

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Autores principales: Boeren, Marlies, Van Breedam, Elise, Buyle-Huybrecht, Tamariche, Lebrun, Marielle, Meysman, Pieter, Sadzot-Delvaux, Catherine, Van Tendeloo, Viggo F., Mortier, Geert, Laukens, Kris, Ogunjimi, Benson, Ponsaerts, Peter, Delputte, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693540/
https://www.ncbi.nlm.nih.gov/pubmed/36423126
http://dx.doi.org/10.3390/v14112517
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author Boeren, Marlies
Van Breedam, Elise
Buyle-Huybrecht, Tamariche
Lebrun, Marielle
Meysman, Pieter
Sadzot-Delvaux, Catherine
Van Tendeloo, Viggo F.
Mortier, Geert
Laukens, Kris
Ogunjimi, Benson
Ponsaerts, Peter
Delputte, Peter
author_facet Boeren, Marlies
Van Breedam, Elise
Buyle-Huybrecht, Tamariche
Lebrun, Marielle
Meysman, Pieter
Sadzot-Delvaux, Catherine
Van Tendeloo, Viggo F.
Mortier, Geert
Laukens, Kris
Ogunjimi, Benson
Ponsaerts, Peter
Delputte, Peter
author_sort Boeren, Marlies
collection PubMed
description Varicella-zoster virus (VZV) infection of neuronal cells and the activation of cell-intrinsic antiviral responses upon infection are still poorly understood mainly due to the scarcity of suitable human in vitro models that are available to study VZV. We developed a compartmentalized human-induced pluripotent stem cell (hiPSC)-derived neuronal culture model that allows axonal VZV infection of the neurons, thereby mimicking the natural route of infection. Using this model, we showed that hiPSC-neurons do not mount an effective interferon-mediated antiviral response following VZV infection. Indeed, in contrast to infection with Sendai virus, VZV infection of the hiPSC-neurons does not result in the upregulation of interferon-stimulated genes (ISGs) that have direct antiviral functions. Furthermore, the hiPSC-neurons do not produce interferon-α (IFNα), a major cytokine that is involved in the innate antiviral response, even upon its stimulation with strong synthetic inducers. In contrast, we showed that exogenous IFNα effectively limits VZV spread in the neuronal cell body compartment and demonstrated that ISGs are efficiently upregulated in these VZV-infected neuronal cultures that are treated with IFNα. Thus, whereas the cultured hiPSC neurons seem to be poor IFNα producers, they are good IFNα responders. This could suggest an important role for other cells such as satellite glial cells or macrophages to produce IFNα for VZV infection control.
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spelling pubmed-96935402022-11-26 Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α Boeren, Marlies Van Breedam, Elise Buyle-Huybrecht, Tamariche Lebrun, Marielle Meysman, Pieter Sadzot-Delvaux, Catherine Van Tendeloo, Viggo F. Mortier, Geert Laukens, Kris Ogunjimi, Benson Ponsaerts, Peter Delputte, Peter Viruses Article Varicella-zoster virus (VZV) infection of neuronal cells and the activation of cell-intrinsic antiviral responses upon infection are still poorly understood mainly due to the scarcity of suitable human in vitro models that are available to study VZV. We developed a compartmentalized human-induced pluripotent stem cell (hiPSC)-derived neuronal culture model that allows axonal VZV infection of the neurons, thereby mimicking the natural route of infection. Using this model, we showed that hiPSC-neurons do not mount an effective interferon-mediated antiviral response following VZV infection. Indeed, in contrast to infection with Sendai virus, VZV infection of the hiPSC-neurons does not result in the upregulation of interferon-stimulated genes (ISGs) that have direct antiviral functions. Furthermore, the hiPSC-neurons do not produce interferon-α (IFNα), a major cytokine that is involved in the innate antiviral response, even upon its stimulation with strong synthetic inducers. In contrast, we showed that exogenous IFNα effectively limits VZV spread in the neuronal cell body compartment and demonstrated that ISGs are efficiently upregulated in these VZV-infected neuronal cultures that are treated with IFNα. Thus, whereas the cultured hiPSC neurons seem to be poor IFNα producers, they are good IFNα responders. This could suggest an important role for other cells such as satellite glial cells or macrophages to produce IFNα for VZV infection control. MDPI 2022-11-14 /pmc/articles/PMC9693540/ /pubmed/36423126 http://dx.doi.org/10.3390/v14112517 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Boeren, Marlies
Van Breedam, Elise
Buyle-Huybrecht, Tamariche
Lebrun, Marielle
Meysman, Pieter
Sadzot-Delvaux, Catherine
Van Tendeloo, Viggo F.
Mortier, Geert
Laukens, Kris
Ogunjimi, Benson
Ponsaerts, Peter
Delputte, Peter
Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α
title Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α
title_full Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α
title_fullStr Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α
title_full_unstemmed Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α
title_short Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α
title_sort activation of interferon-stimulated genes following varicella-zoster virus infection in a human ipsc-derived neuronal in vitro model depends on exogenous interferon-α
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693540/
https://www.ncbi.nlm.nih.gov/pubmed/36423126
http://dx.doi.org/10.3390/v14112517
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