Viral infections of the central nervous system (CNS) often result in encephalitis. Viral encephalitis is a marked risk factor for epilepsy (recurrent seizures). Epilepsy has an incidence of about 1-3% and affects about 2.5 x 106 Americans and more than 5.0 x 107 individuals worldwide. Simplistically, seizures result from imbalances between excitatory and inhibitory inputs within the brain. Encephalitis and resulting damage, particularly to the hippocampus, can alter these connections. Infection-initiated seizure disorders are often refractory to many established antiepileptic drugs. Approximately 30% of individuals with epilepsy are refractory to currently existing anti-seizure medications. Therefore, finding new and novel biological models for epilepsy and potentially new therapeutics are important for the public health. Different virus infections can cause encephalitis that result in acute seizures and later epilepsy. These viruses include herpes viruses such as human herpes virus type-6 as well as influenza viruses, West Nile virus, rotaviruses, adenovirus, respiratory syncytial virus and picornaviruses. For example, the human picornavirus, Enterovirus 71, causes encephalitis where patients often present with acute seizures. A problem that has plagued this field is that a good experimental animal model has not been available to investigate how viral encephalitis and acute seizures can subsequently lead to epilepsy. Previous animal models have used rabbits, rats and mice infected with different viruses. These animals develop encephalitis where acute seizures are observed, but infected animals succumb to the infection or do not subsequently develop spontaneous seizures, making it difficult to investigate the viral etiology of epilepsy. Theiler's murine encephalomyelitis virus (TMEV) is a murine neurotropic picornavirus. We feel it is important to study virus-host interactions using the virus in its naturl host. We have developed a new and novel model where TMEV- infected C57BL/6 mice develop acute seizures between day 3 and 10 post infection. Early infiltrating macrophages producing interleukin (IL)-6 are implicated in the development of acute seizures. Viral antigen positive cell (neurons) are cleared by day 14 and viral genomes are undetectable in the CNS of mice by about day 28 post infection. Therefore, mice recover from the acute seizures and, after a variable latent period, mice start to have recurrent seizures (epilepsy). This is the first infectin driven model of temporal lobe epilepsy.
In Specific Aim 1, we will elucidate the mechanism of the induction of seizures.
In Specific Aim 2, we propose to define the functional link between IL-6 and changes in neuronal excitability.
In Specific Aim 3, we will investigate the effects of wogonin and minocycline, compounds that block (IL-6-producing) macrophage infiltration into the CNS, on both acute seizures and recurrent seizures when administered at various time points post infection with the goal of prevention, interrupting or reversing the occurrence of acute and/or recurrent seizures.

Public Health Relevance

Viral infections of the central nervous system (CNS) result in encephalitis. Viral encephalitis is associated with an increased risk for seizures and the development of epilepsy. We have developed a new and novel mouse model of virus-induced epilepsy. Other animal models for epilepsy use electrical stimulation or neurotoxic substances that kill and/or alter hippocampal neurons within the CNS leading to recurrent seizures. Our viral model is very relevant particularly for testing of new therapeutic strategies that use an anti- inflammatory approach or a combined anti-inflammatory and conventional anti-seizure medication approach. About 30% of individuals are refractory to existing anti-seizure medications. New and novel approaches to this disease are warranted.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Klein, Brian
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Zhan, Jie; Lin, Tsen-Hsuan; Libbey, Jane E et al. (2018) Diffusion Basis Spectrum and Diffusion Tensor Imaging Detect Hippocampal Inflammation and Dendritic Injury in a Virus-Induced Mouse Model of Epilepsy. Front Neurosci 12:77
DePaula-Silva, Ana Beatriz; Sonderegger, F Lynn; Libbey, Jane E et al. (2018) The immune response to picornavirus infection and the effect of immune manipulation on acute seizures. J Neurovirol 24:464-477
Patel, Dipan C; Wallis, Glenna; Dahle, E Jill et al. (2017) Hippocampal TNF? Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy. eNeuro 4:
DePaula-Silva, Ana Beatriz; Hanak, Tyler J; Libbey, Jane E et al. (2017) Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy. J Neuroimmunol 308:30-42
Libbey, Jane E; Cusick, Matthew F; Doty, Daniel J et al. (2017) Complement Components Are Expressed by Infiltrating Macrophages/Activated Microglia Early Following Viral Infection. Viral Immunol 30:304-314
Cusick, Matthew F; Libbey, Jane E; Doty, Daniel J et al. (2017) The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis. J Neurovirol 23:696-703
Libbey, Jane E; Hanak, Tyler J; Doty, Daniel J et al. (2016) NBQX, a highly selective competitive antagonist of AMPA and KA ionotropic glutamate receptors, increases seizures and mortality following picornavirus infection. Exp Neurol 280:89-96
Libbey, Jane E; Doty, Daniel J; Sim, Jordan T et al. (2016) The effects of diet on the severity of central nervous system disease: One part of lab-to-lab variability. Nutrition 32:877-83
Vezzani, Annamaria; Fujinami, Robert S; White, H Steve et al. (2016) Infections, inflammation and epilepsy. Acta Neuropathol 131:211-234
Smeal, R M; Fujinami, R; White, H S et al. (2015) Decrease in CA3 inhibitory network activity during Theiler's virus encephalitis. Neurosci Lett 609:210-5

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