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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-\u03b1 (IFN\u03b1), 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 IFN\u03b1 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 IFN\u03b1. Thus, whereas the cultured hiPSC neurons seem to be poor IFN\u03b1 producers, they are good IFN\u03b1 responders. This could suggest an important role for other cells such as satellite glial cells or macrophages to produce IFN\u03b1 for VZV infection control.<\/jats:p>","DOI":"10.3390\/v14112517","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T02:31:15Z","timestamp":1668479475000},"page":"2517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-\u03b1"],"prefix":"10.3390","volume":"14","author":[{"given":"Marlies","family":"Boeren","sequence":"first","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7471-9064","authenticated-orcid":false,"given":"Elise","family":"Van Breedam","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamariche","family":"Buyle-Huybrecht","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7430-6529","authenticated-orcid":false,"given":"Marielle","family":"Lebrun","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Immunology, GIGA-Infection, Inflammation and Immunity, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5903-633X","authenticated-orcid":false,"given":"Pieter","family":"Meysman","sequence":"additional","affiliation":[{"name":"Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), 2610 Antwerp, Belgium"},{"name":"Adrem Data Lab, Department of Computer Science, University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Biomedical Informatics Research Network Antwerp (Biomina), University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Sadzot-Delvaux","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Immunology, GIGA-Infection, Inflammation and Immunity, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3217-9917","authenticated-orcid":false,"given":"Viggo F.","family":"Van Tendeloo","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Mortier","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8217-2564","authenticated-orcid":false,"given":"Kris","family":"Laukens","sequence":"additional","affiliation":[{"name":"Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), 2610 Antwerp, Belgium"},{"name":"Adrem Data Lab, Department of Computer Science, University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Biomedical Informatics Research Network Antwerp (Biomina), University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benson","family":"Ogunjimi","sequence":"additional","affiliation":[{"name":"Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute, University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), 2610 Antwerp, Belgium"},{"name":"Centre for Health Economics Research & Modelling Infectious Diseases (CHERMID), Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Department of Paediatrics, Antwerp University Hospital, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1892-6499","authenticated-orcid":false,"given":"Peter","family":"Ponsaerts","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3972-616X","authenticated-orcid":false,"given":"Peter","family":"Delputte","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Infla-Med, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1017\/S0950268801005921","article-title":"Epidemiology of varicella zoster virus infection in Canada and the United Kingdom","volume":"127","author":"Brisson","year":"2001","journal-title":"Epidemiol. 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