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 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-alpha (IFN alpha), 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 alpha 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 alpha. Thus, whereas the cultured hiPSC neurons seem to be poor IFN alpha producers, they are good IFN alpha responders. This could suggest an important role for other cells such as satellite glial cells or macrophages to produce IFN alpha for VZV infection control.

Automated summary

This study developed a compartmentalized hiPSC-derived neuronal culture model to mimic natural VZV infection route. The study found that hiPSC-neurons do not mount an effective antiviral response following VZV infection, unlike Sendai virus infection. The cells do not upregulate interferon-stimulated genes and do not produce interferon-alpha. However, exogenous interferon-alpha effectively limits VZV spread in the neuronal cells and promotes upregulation of ISGs.