Virus-Host Interactions that Lead to Epilepsy

Summary

Principal Investigator: Robert S Fujinami
Abstract: DESCRIPTION (provided by applicant): Viral infections of the central nervous system (CNS) can result in encephalitis. Viral encephalitis is a risk factor for epilepsy. Epilepsy has an incidence of about 1 to 3% and affects about 2.5 million Americans and more than 50 million individuals worldwide. Seizures result from imbalances between excitatory and inhibitory inputs within the brain. Encephalitis and resulting damage to the CNS can alter these inputs. Infection- initiated seizure disorders are often refractory to many established anti-epileptic drugs. Approximately 30% of individuals with epilepsy are refractory to currently existing anti-seizure medications. Therefore, finding new biological models for epilepsy and potentially new therapeutics are important for the public health. Different virus infections can cause encephalitis that result in seizures. These viruses include herpes viruses such as human herpes virus type-6, influenza viruses, rotaviruses, adenovirus, respiratory syncytial virus and picornaviruses. For example, the human picornavirus, Enterovirus 71, causes encephalitis where patients often present with seizures. A problem that has plagued this field is that a good experimental animal model is not available to investigate how virus encephalitis can lead to epilepsy. Previous animal models have infected rabbits, rats and mice with different viruses. These animals develop acute encephalitis and develop seizures but succumb to the infection. Theiler's murine encephalomyelitis virus (TMEV) is a neurotropic picornavirus. We have developed a new and novel model where infection of C57BL/6 mice with the Daniels virus (DAV) strain of TMEV leads to acute seizures between days 3 and 10 post infection. Mice recover but after a variable latent period mice start to have spontaneous seizures. This is the first infection driven model of temporal lobe epilepsy. We propose to test in Specific Aim 1 the hypothesis that direct virus infection of pyramidal cells of the hippocampus leads to the development of seizures. In Specific Aim 2 we hypothesize that DAV infection targets a cytokine storm to regions within the CNS that leads to neuronal dysfunction and death. Relevance: Up to 20% of individuals who survive viral encephalitis develop epilepsy. This model is the first infection driven model for epilepsy. Other animal models use electrical stimulation or neurotoxic substances that kill and/or alter neurons in different parts of the brain leading to spontaneous seizures. Our viral model is potentially more relevant particularly for the testing of new therapeutic strategies using an anti- inflammatory approach. As mentioned above about 30% of individuals with epilepsy are refractory to existing anti-seizure medications, and recently the FDA is recommending that warnings be attached to eleven epilepsy drugs disclosing the risk of suicide. Therefore, new approaches are warranted. PUBLIC HEALTH RELEVANCE: Viral infections of the central nervous system 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 neurons within the CNS leading to spontaneous seizures. Our viral model is potentially more relevant particularly for the testing of new therapeutic strategies that use an anti-inflammatory approach. About 30% of individuals with epilepsy are refractory to existing anti-seizure medications, and recently the FDA is recommending that warnings be attached to eleven epilepsy drugs disclosing the risk of suicide. Therefore, new and novel approaches to this disease are warranted.
Funding Period: 2010-01-15 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc Innate but not adaptive immune responses contribute to behavioral seizures following viral infection
    Nikki J Kirkman
    Department of Pathology, University of Utah, Salt Lake City, Utah 84132, USA
    Epilepsia 51:454-64. 2010
  2. pmc Infiltrating macrophages are key to the development of seizures following virus infection
    Matthew F Cusick
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
    J Virol 87:1849-60. 2013
  3. pmc Theiler's murine encephalomyelitis virus contrasts with encephalomyocarditis and foot-and-mouth disease viruses in its functional utilization of the StopGo non-standard translation mechanism
    G Loughran
    Department of Biochemistry, Western Gateway Building, University College Cork, Cork, Ireland
    J Gen Virol 94:348-53. 2013
  4. ncbi The activity within the CA3 excitatory network during Theiler's virus encephalitis is distinct from that observed during chronic epilepsy
    Roy M Smeal
    Department of Pharmacology and Toxicology, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA
    J Neurovirol 18:30-44. 2012
  5. pmc Molecular mimicry as a mechanism of autoimmune disease
    Matthew F Cusick
    Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
    Clin Rev Allergy Immunol 42:102-11. 2012
  6. pmc Once initiated, viral encephalitis-induced seizures are consistent no matter the treatment or lack of interleukin-6
    Jane E Libbey
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
    J Neurovirol 17:496-9. 2011
  7. pmc Lack of correlation of central nervous system inflammation and neuropathology with the development of seizures following acute virus infection
    Jane E Libbey
    Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
    J Virol 85:8149-57. 2011
  8. pmc Interleukin-6, produced by resident cells of the central nervous system and infiltrating cells, contributes to the development of seizures following viral infection
    Jane E Libbey
    Department of Pathology, University of Utah, 30 North 1900 East, 3R330 SOM, Salt Lake City, UT 84132, USA
    J Virol 85:6913-22. 2011
  9. pmc Development of postinfection epilepsy after Theiler's virus infection of C57BL/6 mice
    Kerry Ann A Stewart
    Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah, USA
    J Neuropathol Exp Neurol 69:1210-9. 2010
  10. pmc Role for complement in the development of seizures following acute viral infection
    Jane E Libbey
    Department of Pathology, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA
    J Virol 84:6452-60. 2010

Detail Information

Publications12

  1. pmc Innate but not adaptive immune responses contribute to behavioral seizures following viral infection
    Nikki J Kirkman
    Department of Pathology, University of Utah, Salt Lake City, Utah 84132, USA
    Epilepsia 51:454-64. 2010
    ..To examine the role of innate immunity in a novel viral infection-induced seizure model...
  2. pmc Infiltrating macrophages are key to the development of seizures following virus infection
    Matthew F Cusick
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
    J Virol 87:1849-60. 2013
    ..Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures...
  3. pmc Theiler's murine encephalomyelitis virus contrasts with encephalomyocarditis and foot-and-mouth disease viruses in its functional utilization of the StopGo non-standard translation mechanism
    G Loughran
    Department of Biochemistry, Western Gateway Building, University College Cork, Cork, Ireland
    J Gen Virol 94:348-53. 2013
    ....
  4. ncbi The activity within the CA3 excitatory network during Theiler's virus encephalitis is distinct from that observed during chronic epilepsy
    Roy M Smeal
    Department of Pharmacology and Toxicology, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA
    J Neurovirol 18:30-44. 2012
    ..These differences have implications for the treatment used during the acute infection and after chronic seizures develop...
  5. pmc Molecular mimicry as a mechanism of autoimmune disease
    Matthew F Cusick
    Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
    Clin Rev Allergy Immunol 42:102-11. 2012
    ..Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs, and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases...
  6. pmc Once initiated, viral encephalitis-induced seizures are consistent no matter the treatment or lack of interleukin-6
    Jane E Libbey
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
    J Neurovirol 17:496-9. 2011
    ..Therefore, once seizures develop, the pathological changes are consistent regardless of the treatment or genetic background...
  7. pmc Lack of correlation of central nervous system inflammation and neuropathology with the development of seizures following acute virus infection
    Jane E Libbey
    Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
    J Virol 85:8149-57. 2011
    ..Thus, in H101 mutant infections, it appears that elevated levels of cytokines, rather than neuronal cell death, play the dominant role in seizure induction...
  8. pmc Interleukin-6, produced by resident cells of the central nervous system and infiltrating cells, contributes to the development of seizures following viral infection
    Jane E Libbey
    Department of Pathology, University of Utah, 30 North 1900 East, 3R330 SOM, Salt Lake City, UT 84132, USA
    J Virol 85:6913-22. 2011
    ..Therefore, both resident CNS cells and infiltrating cells are necessary for seizure development...
  9. pmc Development of postinfection epilepsy after Theiler's virus infection of C57BL/6 mice
    Kerry Ann A Stewart
    Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, Utah, USA
    J Neuropathol Exp Neurol 69:1210-9. 2010
    ..Importantly, this model will also be useful to investigate novel therapies for the treatment and prevention of epilepsy...
  10. pmc Role for complement in the development of seizures following acute viral infection
    Jane E Libbey
    Department of Pathology, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA
    J Virol 84:6452-60. 2010
    ..These studies indicate that C3 participates in the induction of acute seizures during viral encephalitis...
  11. ncbi Multiple sclerosis: autoimmunity and viruses
    Matthew F Cusick
    Department of Pathology, University of Utah, Salt Lake City, Utah 84132, USA
    Curr Opin Rheumatol 25:496-501. 2013
    ..The first aspect is the complex interactions between viruses. The second aspect is the proposal of a mechanism by which autoreactive T cells are able to escape thymic selection and potentially recognize self and a pathogen...