Demyelinating diseases constitute a spectrum of immunopathologic syndromes in which, myelin, the fatty covering of nerve cell fibers in the brain, optic nerve, and spinal cord, is destroyed. One of the major diseases associated with degradation of the myelin sheath is multiple sclerosis (MS). Visual disturbances are initial manifestation of MS and optic neuropathy (ON) due to demyelination of optic nerve is a common cause of visual and neurologic dysfunction in young adults diagnosed with MS. ON can be used as an early prognostic factor during the subsequent course of MS. As MS patients have elevated levels of IL-2 in their CSF and sera, which suggests that IL-2 may play a role in the pathology of MS, we explored the effects of infection of mice with a recombinant herpes simplex virus type 1 (HSV-1) expressing murine interleukin-2 (HSV-IL-2). Our Preliminary Studies show that this infection results in demyelination, as determined by visual-evoked cortical potentials (VECPs) and histologic examination at autopsy. In contrast, neither wild- type (wt) HSV infection alone nor HSV-IL-4, nor HSV-IFN-gamma virus (identical to HSV-IL-2 but expressing IL-4 or IFN-gamma instead of IL-2) infection caused demyelination. Analysis of the cellular infiltrates in the brain and spinal cord indicates enhanced activated T cells and IL-12 producing CD11b+ responses in HSV-IL-2 infected group compared with mice infected with control viruses. Based on our preliminary data, we have formulated the working hypothesis that expression of IL-2 by HSV-IL-2 recruits and activates CD8+ T-cells and macrophage infiltrates to the CNS. Following stimulation the CD8+ T cells directly cause demyelination, with the macrophages exacerbating the process by expressing IL-12 and pushing the immune response toward a TH1 response. Our detailed specific aims to further elucidate the biological and immunological mechanisms responsible for HSV-IL-2 induced demyelination include: 1. Define the demyelination process in the CNS of HSV-IL-2-infected mice. 2. Determine the relative roles of IL-2 production and cellular infiltrates in demyelination. 3. Determine if a recombinant HSV-1 expressing IL-4 (HSV-IL-4) can protect against HSV-IL-2-induced demyelination, while a similarly made recombinant virus expressing IFN-gamma is not beneficial.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Shen, Grace L
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Cedars-Sinai Medical Center
Los Angeles
United States
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Dumitrascu, O M; Mott, K R; Ghiasi, H (2014) A comparative study of experimental mouse models of central nervous system demyelination. Gene Ther 21:599-608
Allen, Sariah J; Rhode-Kurnow, Antje; Mott, Kevin R et al. (2014) Interactions between herpesvirus entry mediator (TNFRSF14) and latency-associated transcript during herpes simplex virus 1 latency. J Virol 88:1961-71
Mott, Kevin R; Zandian, Mandana; Allen, Sariah J et al. (2013) Role of interleukin-2 and herpes simplex virus 1 in central nervous system demyelination in mice. J Virol 87:12102-9
Allen, Sariah J; Mott, Kevin R; Wechsler, Steven L et al. (2011) Adaptive and innate transforming growth factor beta signaling impact herpes simplex virus 1 latency and reactivation. J Virol 85:11448-56
Mott, Kevin R; Gate, David; Zandian, Mandana et al. (2011) Macrophage IL-12p70 signaling prevents HSV-1-induced CNS autoimmunity triggered by autoaggressive CD4+ Tregs. Invest Ophthalmol Vis Sci 52:2321-33
Zandian, Mandana; Mott, Kevin R; Allen, Sariah J et al. (2011) IL-2 suppression of IL-12p70 by a recombinant HSV-1 expressing IL-2 induces T-cell auto-reactivity and CNS demyelination. PLoS One 6:e16820
Allen, Sariah J; Mott, Kevin R; Chentoufi, Aziz A et al. (2011) CD11c controls herpes simplex virus 1 responses to limit virus replication during primary infection. J Virol 85:9945-55
Zandian, M; Mott, K R; Allen, S J et al. (2011) Use of cytokine immunotherapy to block CNS demyelination induced by a recombinant HSV-1 expressing IL-2. Gene Ther 18:734-42
Mott, Kevin R; Wechsler, Steven L; Ghiasi, Homayon (2010) Ocular infection of mice with an avirulent recombinant HSV-1 expressing IL-4 and an attenuated HSV-1 strain generates virulent recombinants in vivo. Mol Vis 16:2153-62
Zandian, Mandana; Belisle, Raelene; Mott, Kevin R et al. (2009) Optic neuritis in different strains of mice by a recombinant HSV-1 expressing murine interleukin-2. Invest Ophthalmol Vis Sci 50:3275-82

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