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Project

AT-DNA sensing & autophagy as major features in the development of chickenpox-associated neurological complications.

Varicella-zoster virus (VZV) causes chickenpox in children and remains latent in neural ganglia afterwards. VZV can cause encephalitis or cerebellitis during both the acute and subacute phases of chickenpox. After resolution of chickenpox, VZV can reactivate from its latent state and cause herpes zoster. Moreover, VZV reactivation is believed to be able to cause stroke in children. The pathophysiology underlying all of these central nervous system VZV complications remains largely unknown so far. In this project, we aim to deepen our understanding regarding two factors that might cause a genetic predisposition in humans for the development of chickenpox-associated neurological complications. Preliminary data from our lab previously showed that mutations in RNA polymerase III (POL III) cause a defect in VZV sensing (via AT-DNA "recognition") in blood cells and consequently cause a reduced control of VZV proliferation. In this project, we first aim to show that following primary VZV infection, glial cells, which are immune-responsive cells in the central nervous system, recognize VZV and subsequently produce protective cytokines. Moreover, we will assess whether mutations in AT-DNA sensor POL III in children with encephalitis, cerebellitis or stroke/vasculitis due to chickenpox have a defective recognition of VZV and subsequently increased VZV proliferation in central neurons. We will do this by differentiating induced pluripotent stem cells (iPSC) from patients and controls into neurons and glial cells, and subsequently infecting these with VZV. This will lead to a simultaneous analysis of VZV dynamics in neurons and cytokine production by glial cells.Preliminary data from our labs and others have shown that the cellular process called autophagy, important for protein processing, might be involved in cellular VZV dynamics as inhibition of autophagy led to reduced VZV proliferation. In this project, we aim to further address this potential pathogenic route by experimentally inhibiting autophagy in iPSC-derived neurons from healthy controls and measuring the subsequent effects on VZV dynamics. In addition, we noted that 3/9 cerebellitis patients had a mutation in the autophagy-associated gene TBC19DB. In a first exploration, we will assess how autophagy is affected by this mutation and whether this influences VZV proliferation in monocytes from these patients and controls.
Date:1 Oct 2018  →  Today
Keywords:STEM CELL PHYSIOLOGY, INFECTIONS
Disciplines:Immunology, Morphological sciences, Neurosciences, Microbiology, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing