Varicella-zoster virus is an alpha-herpesvirus that causes varicella and zoster. Infection of T cells allows VZV transfer from the respiratory tract to skin and the typical herpes zoster rash results from axonal transport after VZV reactivation in neurons. Our research program investigates the mechanisms of VZV take-over of its target cells, focusing on infection of primary human tonsil T cells and adult skin xenografts in the severe combined immunodeficiency (SCIO) mouse model. We plan to pursue our longstanding objective to understand of VZV pathogenesis in new directions that are designed to determine the role of activation of protein kinase R in VZV infection, the effects of complement as an innate defense against VZV infection of tonsil T cells and VZV countermeasures, and glycoprotein-mediated mechanisms of VZV entry into T cells. This work is expected to provide new knowledge about the takeover of host cell signaling pathways by VZV to support its replication, the regulation of VZV pathogenesis by innate host responses and how VZV overcomes these barriers, and the functions of VZV glycoproteins during infection of differentiated human cells, all of which are critical for VZV infection of the human host. RELEVANCE (See instructions):