By 2050, the number of Americans 65 years and older is projected to be 83.7 million, and the burden of diseases and healthcare costs will be staggering. An important cause of multi-system disease in the elderly is varicella zoster virus (VZV) reactivation. More than 95% of humans harbor latent VZV in their ganglia following primary infection (varicella, chickenpox) and 50% of them will reactivate VZV by 85 years of age. Serious complications of VZV reactivation include postherpetic neuralgia (PHN), giant cell arteritis, burning mouth syndrome, stroke, multi-infarct dementia, blindness, esophagitis, pneumonitis, and gastroparesis. Thus, VZV reactivation affects multiple organs. VZV-induced persistent inflammation has emerged as an important pathologic contributor in most of these disorders. The mechanism(s) by which inflammatory cells persist in infected tissue is unknown; however human vascular cells infected in vitro with VZV show downregulated expression of programmed death ligand 1 (PD-L1) and major histocompatibility complex 1. Decreased PD-L1 expression contributes to persistent inflammation in autoimmune diseases, raising the possibility that VZV- induced downregulation of PD-L1 also contributes to persistent inflammation. Since VZV is an exclusively human virus, we will investigate the role of virus-induced PD-L1 dysregulation across multiple, clinically relevant tissues in non-human primates infected with simian varicella virus (SVV), a model that we developed in the last two decades. SVV, the primate counterpart of VZV, causes varicella on primary infection, establishes latency in ganglia, and reactivates later to produce zoster and multi-system disease. Preliminary results reveal SVV antigen- and CXCL10-induced T cell infiltration in ganglia 4 months after tacrolimus- induced SVV reactivation in rhesus macaques, similar to the chronic ganglionitis seen in PHN patients. Like VZV, SVV infection of rhesus fibroblasts in culture leads to decreased PD-L1 expression. Thus, we hypothesize that after SVV reactivation, viral antigen and activated immune cells persist in multiple tissues for months, in part due to dysregulation of PD-L1, thereby contributing to clinical disease seen in inflamed tissue in the elderly. To test our hypothesis, we will analyze the extent of SVV infection and associated inflammation in multiple tissues longitudinally after zoster (Aim 1). We will also correlate the composition, activation state and function of immune cells in multiple tissues longitudinally after zoster with the presence of SVV and inflammation (Aim 2). Overall, these studies in the non-human primate model of VZV reactivation will provide insight into multiple virus-infected tissues, not available in humans, to elucidate the mechanisms of viral persistence and inflammation, information that will be translatable to development of new intervention strategies to inhibit multi-system disease caused by VZV in elderly humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG032958-13
Application #
10097969
Study Section
Special Emphasis Panel (ZAG1)
Project Start
2009-03-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
13
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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