Virus-Host Interactions that Lead to Epilepsy

描述（申请人提供）：中枢神经系统（CNS）的病毒感染可导致脑炎。病毒性脑炎是癫痫的一个危险因素。癫痫的发病率约为1%至3%，影响约250万美国人和全世界5000多万人。癫痫发作是由大脑内兴奋性和抑制性输入的不平衡引起的。脑炎和由此引起的中枢神经系统损伤可以改变这些输入。感染引发的癫痫性疾病通常对许多已建立的抗癫痫药物是难治的。大约30%的癫痫患者对现有的抗癫痫药物无效。因此，寻找新的癫痫生物学模型和潜在的新疗法对公共卫生很重要。不同的病毒感染可引起脑炎，并导致癫痫发作。这些病毒包括疱疹病毒，如人类疱疹病毒6型、流感病毒、轮状病毒、腺病毒、呼吸道合胞病毒和小核糖核酸病毒。例如，人类小核糖核酸病毒肠病毒71型可引起脑炎，患者通常表现为癫痫发作。困扰这一领域的一个问题是，没有一个好的实验动物模型来研究病毒性脑炎如何导致癫痫。之前的动物模型已经用不同的病毒感染了兔子、大鼠和小鼠。这些动物会出现急性脑炎和癫痫发作，但会死于感染。泰勒鼠脑脊髓炎病毒（TMEV）是一种嗜神经小核糖核酸病毒。我们已经建立了一种新的模型，C57BL/6小鼠感染丹尼尔斯病毒（DAV）株TMEV导致感染后3天至10天急性癫痫发作。小鼠会恢复，但经过一段可变潜伏期后，小鼠开始出现自发性癫痫发作。这是第一个感染驱动的颞叶癫痫模型。我们建议在特异性目标1中测试直接病毒感染海马锥体细胞导致癫痫发作的假设。在Specific Aim 2中，我们假设DAV感染的目标是中枢神经系统内的细胞因子风暴，导致神经元功能障碍和死亡。相关性：高达20%的病毒性脑炎患者会发展为癫痫。该模型是第一个感染驱动的癫痫模型。其他动物模型使用电刺激或神经毒性物质杀死和/或改变大脑不同部位的神经元，导致自发性癫痫发作。我们的病毒模型是潜在的更相关，特别是测试新的治疗策略使用抗炎方法。如上所述，大约30%的癫痫患者对现有的抗癫痫药物是难治的，最近FDA建议在11种癫痫药物上附加警告，披露自杀风险。因此，有必要采用新的方法。

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.