Activation of Interferon-Stimulated Genes following Varicella-Zoster Virus Infection in a Human iPSC-Derived Neuronal In Vitro Model Depends on Exogenous Interferon-α
Marlies Boeren,
Elise Van Breedam,
Tamariche Buyle-Huybrecht,
Marielle Lebrun,
Pieter Meysman,
Catherine Sadzot-Delvaux,
Viggo F. Van Tendeloo,
Geert Mortier,
Kris Laukens,
Benson Ogunjimi,
Peter Ponsaerts,
Peter Delputte
Affiliations
Marlies Boeren
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, Belgium
Elise Van Breedam
Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium
Tamariche Buyle-Huybrecht
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, Belgium
Marielle Lebrun
Laboratory of Virology and Immunology, GIGA-Infection, Inflammation and Immunity, University of Liège, 4000 Liège, Belgium
Pieter Meysman
Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), 2610 Antwerp, Belgium
Catherine Sadzot-Delvaux
Laboratory of Virology and Immunology, GIGA-Infection, Inflammation and Immunity, University of Liège, 4000 Liège, Belgium
Viggo F. Van Tendeloo
Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium
Geert Mortier
Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, 2610 Antwerp, Belgium
Kris Laukens
Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), 2610 Antwerp, Belgium
Benson Ogunjimi
Antwerp Center for Translational Immunology and Virology (ACTIV), Vaccine and Infectious Disease Institute, University of Antwerp, 2610 Antwerp, Belgium
Peter Ponsaerts
Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, 2610 Antwerp, Belgium
Peter Delputte
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, 2610 Antwerp, Belgium
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.
