Biological Relevance of in Vitro Cellular Models to Study Varicella-Zoster Virus—host Cell Interactome: Current Limitations and Future Perspectives

SUMMARYWith varicella-zoster virus (VZV) being a strictly human-specific pathogen, in vitro cell culture models to study the VZV-host cell interactome predominantly rely on the use of primary human cells, immortalized cell lines, and-more recently-stem cell-derived models. In this work, based on literature reports published within the past 15 years, we attempted to summarize major lessons learned from in vitro VZV research, with a specific focus on whether and how a variety of host cells respond upon VZV infection at the cellular level. Following this specific approach, we describe the cellular events occurring following VZV infection in a neural cell type context, an immune cell type context, and a skin cell type context. Highly relevant, and for sure subject to the development of future VZV research, cell types within each of the three compartments reviewed display similarities but also significant differences in cellular response to VZV infection. Clearly, these need further clarification on a cell-type and/or VZV strain-specific level. Finally, to increase physiological relevance, we propose an integrated approach for future VZV-host cell interactome studies on a systems level by using advanced human-induced pluripotent stem cell-derived skin, peripheral, and central nervous system compartments that can be complemented with an isogenic immune cell component. Combined with the implementation of state-of-the-art multi-omics analyses, as well as electrophysiological recordings, this next-generation toolbox for advanced virus-host cell interactome studies may help to elucidate important aspects of VZV biology, including the suggested link between VZV pathology and neurodegenerative diseases.