The Faculty of Medicine and Health Sciences is seeking to fill a full-time (100%) vacancy in the Vaccine and Infectious Disease Institute for a
Doctoral Grant by the University Research Fund (BOF) in the area of “AT-DNA sensing & autophagy as major features in the development of chickenpox-associated neurological complications”
Varicella-zoster virus (VZV) causes chickenpox in children and can cause encephalitis, cerebellitis or stroke during both the acute and subacute phases of chickenpox. The pathophysiology underlying all of these central nervous system VZV complications remains largely unknown so far.
We 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 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. In addition, preliminary data from our labs and others have shown that autophagy might be involved in cellular VZV dynamics. In this project, we also 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.
Experimentally, this translational project will therefore use a wide array of techniques, including the development and maintenance of iPSC-derived neuronal cell cultures, VZV production and infection monitoring, ELISA, western blotting, whole exome sequencing and autophagy modulation.
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