The goal of this program project (PPG) is to prevent serious neurological disease in the elderly caused by reactivation of the ubiquitous highly neurotropic varicella zoster virus (VZV). The PPG contains 3 scientific projects and supportive administrative and scientific cores. Primary infection by varicella zoster virus (VZV) usually causes varicella, after which virus becomes latent in ganglionic neurons along the entire neuraxis. With aging, a declining cell-mediated immunity to VZV leads to virus reactivation, manifesting as herpes zoster (shingles) characterized by pain and rash restricted to 1-3 dermatomes. The incidence and severity of zoster is also increased in organ transplant recipients and patients with cancer or AIDS. Zoster is frequently complicated by chronic pain (postherpetic neuralgia), paralysis, blindness and stroke. Currently, -1,000,000 Americans develop zoster annually. Oka VZV vaccine reduces the incidence of zoster by 50%, but even if every American over age 60 was vaccinated, >500,000 cases would still occur every year. This PPG will: determine the emerging role of multifocal VZV vasculopathy as an important cause of vision loss and headaches in the elderly, examine mechanisms by which VZV exits latency to cause disease and identify key virus-host interactions involved in immunity and spread of infection. Project 1, an exciting new translational project, will identify clinical, laboratory and pathological features of a form of multifocal VZV vasculopathy that mimics giant cell arteritis (GCA), a cause of vision loss and headache in the elderly, findings that are likely to shift the current clinical practice paradigm. Project 2 tests the hypothesis that VZV reactivation initially involves generalized deregulation of latent gene transcription followed by conditions conducive to virus DNA replication and release of infectious virus. Project 3 uses an animal model to determine critical virus-host immune cell interactions that contribute to viral pathogenesis. The combined studies will provide valuable clinical, laboratory and pathological data needed to diagnose and treat a form of multifocal VZV vasculopathy that mimics giant cell arteritis and will provide the needed molecular groundwork for efforts to prevent the cascade of events leading to VZV reactivation, a cause of serious neurologic disease, particularly in the rapidly increasing elderly and immunocompromised populations. This proposal melds the skills and strategies of MDs, PhDs and DVMs with expertise in clinical neurology, molecular virology and immunology.

Public Health Relevance

Varicella zoster virus (VZV) is a ubiquitous highly neurotropic exclusively human alphaherpesvirus that causes significant morbidity and mortality. The goal of this program project is to expand the spectrum of disease caused by VZV and determine mechanisms of latency and pathogenesis, always focusing on preventing acute and chronic neurologic disease produced by virus reactivation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG032958-06
Application #
8608702
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (02))
Program Officer
Mackiewicz, Miroslaw
Project Start
2009-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$1,968,529
Indirect Cost
$525,194
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Cohrs, Randall J; Badani, Hussain; Baird, Nicholas L et al. (2017) Induction of varicella zoster virus DNA replication in dissociated human trigeminal ganglia. J Neurovirol 23:152-157
Ouwendijk, Werner J D; van Veen, Suzanne; Mahalingam, Ravi et al. (2017) Simian varicella virus inhibits the interferon gamma signalling pathway. J Gen Virol :
Nagel, Maria A; Jones, Dallas; Wyborny, Ann (2017) Varicella zoster virus vasculopathy: The expanding clinical spectrum and pathogenesis. J Neuroimmunol 308:112-117
Gilden, Don; White, Teresa; Boyer, Philip J et al. (2016) Varicella Zoster Virus Infection in Granulomatous Arteritis of the Aorta. J Infect Dis 213:1866-71
Jones, Dallas; Alvarez, Enrique; Selva, Sean et al. (2016) Proinflammatory cytokines and matrix metalloproteinases in CSF of patients with VZV vasculopathy. Neurol Neuroimmunol Neuroinflamm 3:e246
Gilden, Don; White, Teresa; Khmeleva, Nelly et al. (2016) Blinded search for varicella zoster virus in giant cell arteritis (GCA)-positive and GCA-negative temporal arteries. J Neurol Sci 364:141-3
Nagel, Maria A; Gilden, Don (2016) Burning mouth syndrome associated with varicella zoster virus. BMJ Case Rep 2016:
Gilden, Don; Nagel, Maria A (2016) Varicella zoster virus and giant cell arteritis. Curr Opin Infect Dis 29:275-9
Gilden, Don; Grose, Charles; White, Teresa et al. (2016) Successful antiviral treatment after 6years of chronic progressive neurological disease attributed to VZV brain infection. J Neurol Sci 368:240-2

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