This proposal describes a 5-year research and training program for Dr. Maria Nagel to develop an independent academic career studying varicella zoster virus (VZV) infection, latency and reactivation. More than 90% of the population is infected with VZV before adolescence (Seward et al., 2000). As cell-mediated immunity to VZV declines in elderly and immunocompromised individuals (Gershon and Steinberg, 1981;Burke et al., 1982), VZV reactivates and causes multiple serious neurological diseases including zoster (shingles) frequently complicated by chronic pain (postherpetic neuralgia), stroke, blindness and spinal cord disease. VZV replicates in all human cells except neurons where virus becomes latent. The mechanisms that determine productive versus latent infection are unclear, but likely involve cell type-specific interactions of viral proteins and host cell antiviral defense mechanisms. Recent studies on herpesviruses show that viral proteins interact with antiviral promyelocytic leukemia nuclear bodies (PML-NBs) in the host and that the outcome of the interaction contributes to productive infection versus latency (Everett and Chelbi-Alix, 2007);in addition, the structure of PML-NBs is dramatically altered in cells undergoing mitosis compared to PML-NB stability in post-mitotic cells such as neurons (Dellaire et al., 2006a). Based on these observations, we hypothesize that the outcome of VZV infection (lysis versus latency and subsequent reactivation) results from cell type-specific interactions of VZV proteins with the host cell's antiviral PML-NBs. To test this hypothesis, we will:
(Aim 1) analyze non-neuronal cells productively-infected with VZV for interactions of PML-NBs with VZV gene 61 protein (VZV 61p), which is homologous to herpesvirus proteins known to interact with PML-NBs, and with VZV gene 63 protein (VZV 63p), the most prevalent and abundant VZV protein expressed in latently-infected human ganglia, using immunochemistry and confocal microscopy. The effects of PML, VZV 61p, and VZV 63p overexpression and underexpression on VZV gene expression and viral titers will also be examined;
(Aim 2) analyze latently-infected human ganglionic neurons obtained at autopsy for interactions of PML-NBs with VZV 61p and VZV 63p using techniques in Aim 1 and fluorescent in situ hybridization to detect VZV DNA in ganglionic neurons;
and (Aim 3) analyze human ganglion neurons obtained at autopsy during early explant-induced reactivation for interactions of PML-NBs with VZV61p and VZV 63p using techniques from Aim 2. During the award period, Dr. Nagel will be promoted to Assistant Professor in the Department of Neurology, which provides a fruitful environment for physician-scientists. Training will be enhanced with didactic courses in molecular virology, bioethics, and statistical analysis. She will devote 80% effort to research and 20% to patient care/clinical teaching. She will apply for an independent R01 award during her 4th year of training. Her primary scientific mentor will be Dr. Randall Cohrs, Research Professor of Neurology at the University of Colorado Denver, a basic research scientist and one of the world's experts on VZV pathogenesis. Despite the development of a zoster vaccine, even if every American over age 60 received zoster vaccine, more than 500,000 new cases of zoster will occur annually. Thus, an understanding of viral and host cell interactions leading to VZV latency and reactivation will provide the basis for strategies to prevent serious neurological disease caused by VZV.

Public Health Relevance

PROJECT NARRATIVE: Neurological diseases caused by neurotropic viruses are a major cause of morbidity and mortality worldwide. Varicella zoster virus causes more neurological disease than any other neurotropic virus, yet the interactions between VZV and the host cell that determine whether the virus establishes productive versus latent infection are largely unknown. A better understanding of these interactions and how they lead to disease is prerequisite in the rational design of strategies to prevent and treat neurological disease produced by VZV and other herpesviruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS067070-04
Application #
8320861
Study Section
NST-2 Subcommittee (NST)
Program Officer
Wong, May
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$187,380
Indirect Cost
$13,880
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Nagel, Maria A (2014) Varicella zoster virus vasculopathy: clinical features and pathogenesis. J Neurovirol 20:157-63
Nagel, Maria A; Gilden, Don (2014) Neurological complications of varicella zoster virus reactivation. Curr Opin Neurol 27:356-60
Nagel, Maria A; Khmeleva, Nelly; Choe, Alexander et al. (2014) Varicella zoster virus (VZV) in cerebral arteries of subjects at high risk for VZV reactivation. J Neurol Sci 339:32-4
Teodoro, Tiago; Nagel, Maria A; Geraldes, Ruth et al. (2014) Biopsy-negative, varicella zoster virus (VZV)-positive giant cell arteritis, zoster, VZV encephalitis and ischemic optic neuropathy, all in one. J Neurol Sci 343:195-7
Liberman, Ava L; Nagel, Maria A; Hurley, Michael C et al. (2014) Rapid development of 9 cerebral aneurysms in varicella-zoster virus vasculopathy. Neurology 82:2139-41
Nagel, Maria A; Gilden, Don (2014) Update on varicella zoster virus vasculopathy. Curr Infect Dis Rep 16:407
Nagel, Maria; Gilden, Don (2014) Editorial commentary: varicella zoster virus infection: generally benign in kids, bad in grown-ups. Clin Infect Dis 58:1504-6
Gilden, Don; Nagel, Maria A; Cohrs, Randall J (2014) Varicella-zoster. Handb Clin Neurol 123:265-83
Nagel, Maria A; Rempel, April; Huntington, Jonathon et al. (2014) Frequency and abundance of alphaherpesvirus DNA in human thoracic sympathetic ganglia. J Virol 88:8189-92
Nagel, Maria A; James, Stephanie F; Traktinskiy, Igor et al. (2014) Inhibition of phosphorylated-STAT1 nuclear translocation and antiviral protein expression in human brain vascular adventitial fibroblasts infected with varicella-zoster virus. J Virol 88:11634-7

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