Giant cell arteritis (GCA), the most common systemic vasculitis in individuals >50 years of age, presents with symptoms and signs including unilateral headache, temporal artery (TA) tenderness, polymyalgia rheumatica, fatigue, weight loss and elevated serum inflammatory markers. Diagnosis is confirmed by TA biopsy showing transmural inflammation, medial damage and giant and/or epithelioid cells (GCA-positive). Corticosteroid treatment is often ineffective and patients develop blindness and stroke. By 2050, a predicted 1.82 million elderly individuals will develop GCA, of which 36,500 will lose vision resulting total projected cost to the USA health system of $83.8 billion with $6.5 billion for steroid-induced fracture, $1.1 billion for initial inpatient management of GCA-associated visual impairment and $76.2 million for ongoing support of elderly with visual impairment. We have shown GCA is a form of varicella zoster virus (VZV) vasculopathy based on: (1) identical granulomatous inflammation in GCA-positive TAs and cerebral arteries of intracranial VZV vasculopathy, (2) presence of VZV antigen, DNA and herpesvirus particles in up to 70% GCA-positive TAs and in VZV-infected cerebral arteries, (3) importance of the outermost arterial layer (adventitia) as the site of initial inflammation and VZV infection consistent with virus deposition from nerve fibers that terminate in adventitia, (4) upregulation of similar cytokines (IL-6, IL-8 and VEGF), and (5) improvement of GCA with acyclovir treatment. However, the critical question remains: how is a chronic proinflammatory environment maintained in the vessel wall, especially in vascular adventitial fibroblasts, with a small amount of VZV relative to inflammation? Our preliminary data showing VZV infection induces proinflammatory cytokines in VZV-infected vascular adventitial fibroblasts and bystander cells in vitro and in vivo, along with the similarities between adventitial fibroblasts in GCA and pulmonary arterial hypertension forms the basis of our hypothesis that VZV infection of vascular adventitial fibroblasts contributes to GCA by initiating epigenetic reprogramming resulting in continued transcription of host genes associated with proinflammatory cytokine production. We will test this hypothesis by profiling the inflammatory phenotype (Aim 1) and transcriptome (Aim 2) of adventitial fibroblasts from GCA- positive and control TAs to determine if VZV infection can induce these changes in gene expression (Aims 1 and 2). The epigenetic modification of regulatory histones and inflammatory transcription factors associated with host genes accounting for the proinflammatory environment will be determined to provide a mechanism for their chronic activation (Aim 3). Upon successful completion of these aims, our multi-disciplinary team will present a new concept by applying advanced technology and develop new algorithms to manage large data sets to show that vascular adventitial fibroblasts can undergo an epigenetically fixed phenotypic change resulting in chronic inflammation that can lead to new therapies to reverse epigenetic modifications that result from VZV infection in the elderly population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG032958-11
Application #
9491548
Study Section
Special Emphasis Panel (ZAG1)
Project Start
2009-03-01
Project End
2024-12-31
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
11
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Como, Christina N; Pearce, Catherine M; Cohrs, Randall J et al. (2018) Interleukin-6 and type 1 interferons inhibit varicella zoster virus replication in human neurons. Virology 522:13-18
Mahalingam, Ravi; Kaufer, Benedikt B; Ouwendijk, Werner J D et al. (2018) Attenuation of Simian Varicella Virus Infection by Enhanced Green Fluorescent Protein in Rhesus Macaques. J Virol 92:
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
Cohrs, Randall J; Lee, Katherine S; Beach, Addilynn et al. (2017) Targeted Genome Sequencing Reveals Varicella-Zoster Virus Open Reading Frame 12 Deletion. J Virol 91:
Nagel, Maria A; Jones, Dallas; Wyborny, Ann (2017) Varicella zoster virus vasculopathy: The expanding clinical spectrum and pathogenesis. J Neuroimmunol 308:112-117
Ouwendijk, Werner J D; van Veen, Suzanne; Mahalingam, Ravi et al. (2017) Simian varicella virus inhibits the interferon gamma signalling pathway. J Gen Virol :
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; Boyer, Philip J et al. (2016) Varicella Zoster Virus Infection in Granulomatous Arteritis of the Aorta. J Infect Dis 213:1866-71
Keller, Amy C; Badani, Hussain; McClatchey, P Mason et al. (2016) Varicella zoster virus infection of human fetal lung cells alters mitochondrial morphology. J Neurovirol 22:674-682
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

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