T-cell receptor diversity and AT-rich DNA sensing by glial cells as key features in controlling neurological varicella-zoster virus infections.

Varicella-zoster virus (VZV) causes chickenpox in children and remains latent in neural ganglia afterwards. VZV reactivation causes shingles (herpes zoster, HZ). In WP1, we will prospectively recruit 150 HZ patients and 150 controls. We aim to show that the affinity of Major Histocompatibility Complex class I (MHC-I) molecules to bind VZV peptides, as needed for the development of VZV-specific Tcells, is reduced in HZ patients. Next, we will assess whether this reduced affinity leads to a reduced diversity of T-cell receptors directed against VZV, thereby implying a narrower scope of protection against VZV, or at least against several key VZV proteins. Finally, we will develop induced pluripotent stem cells (iPSC) derived sensory neurons from healthy individuals, infect these with VZV and assess whether addition of VZV-protein specific T-cells affects the control of VZV reactivation. In WP2, 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-rich DNA sensor POL III in children with encephalitis, cerebellitis or stroke/vasculitis due to chickenpox cause a defective recognition of VZV and subsequently increased VZV proliferation in central neurons. We will do this by differentiating iPSC from patients and controls into neurons and glial cells, and subsequently infecting these with VZV.

Keywords:VARICELLA-ZOSTER VIRUS

Disciplines:Public health care, Public health sciences, Public health services