Abstract
Human alphaherpesviruses varicella zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) usually cause only self-limiting disease. However, in some cases the infection spreads to the central nervous system (CNS) where it can affect multiple cell types and can cause severe CNS complications like encephalitis. Even though preceding studies have aimed to understand virus-host interactions, these cellular models failed to replicate a genuine multicellular dimension of an in vitro CNS-like environment. For my PhD project proposal, I will apply a mature immunocompetent hiPSC-derived neurospheroid (NSPH) model containing isogenic neurons, astrocytes and microglia in order to represent a CNS-like environment to study the molecular, cellular and functional alterations associated with HSV-1 and VZV single infections, and to a further extent HSV-1 and VZV co-/superinfections, as observed in the majority of the human population. Hereto, a multimodal analysis toolbox will be applied, including state-of-the-art electrophysiological, transcriptomic and proteomic analyses, further supported with cellular and immunocytochemical analyses. With this project I aim to advance the fundamental knowledge regarding virus-specific induced mechanisms that lead to CNS dysfunction, both on functional (e.g. electrophysiology) and cellular (e.g. immune response, cellular stress) level, and thereby paving the way for a new era in human viral neuro-immune pathology research.
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