Virus-Host Interactions that Lead to Epilepsy

描述（由申请方提供）：中枢神经系统（CNS）的病毒感染通常导致脑炎。病毒性脑炎是癫痫（反复发作）的一个显著危险因素。癫痫的发病率约为1-3%，影响约2.5 x 106个美国人和超过5.0 x 107个全球个体。简单地说，癫痫发作是由大脑内兴奋性和抑制性输入之间的不平衡引起的。大脑的兴奋和由此产生的损伤，特别是海马体的损伤，会改变这些连接。许多已确定的抗癫痫药物通常对癫痫发作性疾病难治。大约30%的癫痫患者对现有的抗癫痫药物难以治疗。因此，我们认为， 发现新的和新颖的癫痫生物学模型和潜在的新疗法对于公共健康是重要的。 不同的病毒感染可引起脑炎，导致急性癫痫发作和后来的癫痫。这些病毒包括疱疹病毒，如人疱疹病毒6型以及流感病毒、西尼罗河病毒、轮状病毒、腺病毒、呼吸道合胞病毒和小核糖核酸病毒。例如，人小核糖核酸病毒，肠道病毒71，引起脑炎，患者经常出现急性癫痫发作。困扰这一领域的一个问题是，还没有一个好的实验动物模型来研究病毒性脑炎和急性癫痫发作如何导致癫痫。以前的动物模型使用了感染不同病毒的兔子、大鼠和小鼠。这些动物在观察到急性癫痫发作时发生脑炎，但受感染的动物死于感染或随后不发生自发性癫痫发作，使得难以研究癫痫的病毒病因。泰勒氏鼠脑脊髓炎病毒（Theiler's murine encephalomyelitis virus，TMEV）是一种鼠嗜神经性小核糖核酸病毒。我们认为利用病毒在其自然宿主中研究病毒-宿主相互作用是重要的。我们已经开发了一种新的和新颖的模型，其中TMEV感染的C57 BL/6小鼠在感染后第3天和第10天之间发生急性癫痫发作。产生白细胞介素（IL）-6的早期浸润巨噬细胞与急性癫痫发作的发生有关。病毒抗原阳性细胞（神经元）在第14天被清除，并且病毒基因组在感染后约28天在小鼠的CNS中不可检测。因此，小鼠从急性癫痫发作中恢复，并且在可变的潜伏期之后，小鼠开始具有复发性癫痫发作（癫痫）。这是第一个感染驱动的颞叶癫痫模型。在具体目标1中，我们将阐明诱导癫痫发作的机制。在具体目标2中，我们建议定义IL-6和神经元兴奋性变化之间的功能联系。在具体目标3中，我们将研究汉黄芩素和米诺环素（阻断（产生IL-6）的巨噬细胞浸润到CNS的化合物）在感染后不同时间点给药时对急性癫痫发作和复发性癫痫发作的影响，目的是预防、中断或逆转急性和/或复发性癫痫发作的发生。

DESCRIPTION (provided by applicant): 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.