Virus-Host Interactions that Lead to Epilepsy

描述（由申请方提供）：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超过5000万人。癫痫发作是由于大脑内兴奋性和抑制性输入之间的不平衡引起的。中枢神经系统的增强和由此产生的损害可以改变这些输入。感染引发的癫痫发作通常对许多已建立的抗癫痫药物无效。大约30%的癫痫患者对现有的抗癫痫药物难以治疗。因此，寻找新的癫痫生物学模型和潜在的新治疗方法对公共卫生至关重要。 不同的病毒感染可引起脑炎，导致癫痫发作。这些病毒包括疱疹病毒，如人疱疹病毒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，肠道病毒71，引起脑炎，患者经常出现癫痫发作。一直困扰这一领域的一个问题是，没有一个很好的实验动物模型来研究病毒性脑炎如何导致癫痫。以前的动物模型用不同的病毒感染了兔子、大鼠和小鼠。这些动物发展成急性脑炎和癫痫发作，但死于感染。Theiler小鼠脑脊髓炎病毒（TMEV）是一种嗜神经性小核糖核酸病毒。我们已经开发了一种新的和新颖的模型，其中用TMEV的Daniels病毒（DAV）株感染C57 BL/6小鼠导致感染后3至10天之间的急性癫痫发作。小鼠恢复，但在可变的潜伏期后，小鼠开始自发癫痫发作。这是第一个感染驱动的颞叶癫痫模型。我们建议在特定目标1中测试海马锥体细胞的直接病毒感染导致癫痫发作的假设。在特定目标2中，我们假设DAV感染将细胞因子风暴靶向CNS内的区域，导致神经元功能障碍和死亡。 相关性：高达20%的病毒性脑炎幸存者发展为癫痫。该模型是癫痫的第一个感染驱动模型。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。我们的病毒模型可能更相关，特别是对于使用抗炎方法的新治疗策略的测试。如上所述，大约30%的癫痫患者对现有的抗癫痫药物难以治疗，最近FDA建议对11种癫痫药物附加警告，披露自杀风险。因此，需要采取新的办法。 公共卫生相关性：中枢神经系统的病毒感染导致脑炎。病毒性脑炎与癫痫发作和癫痫发展的风险增加有关。我们开发了一种新的病毒诱导癫痫的小鼠模型。癫痫的其他动物模型使用电刺激或神经毒性物质，其杀死和/或改变CNS内的神经元，导致自发性癫痫发作。我们的病毒模型可能更相关，特别是对于使用抗炎方法的新治疗策略的测试。大约30%的癫痫患者对现有的抗癫痫药物无效，最近FDA建议对11种癫痫药物附加警告，披露自杀风险。因此，有必要对这种疾病采取新的和新颖的方法。

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.