Virus-Host Interactions that Lead to Epilepsy

导致癫痫的病毒-宿主相互作用

• 批准号: 8196959
• 负责人: Robert S Fujinami
• 金额: $ 32.05万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196959
• 关键词: Acute; Adenoviruses; Affect; American; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiepileptic Agents; Apoptosis; Behavior; Biological Models; Brain; Brain Part; C57BL/6 Mouse; Cells; Central Nervous System Infections; Central Nervous System Viral Diseases; Cessation of life; Chimera organism; DNA Nucleotidylexotransferase; Development; Disease; Electric Stimulation; Encephalitis; Encephalitis Viruses; Enterovirus 71; Epilepsy; Epileptogenesis; Etiology; Experimental Animal Model; Family Picornaviridae; Herpesviridae; Hippocampus (Brain); Human; Immune; Immune response; Immunodeficient Mouse; Incidence; Individual; Infection; Inflammation; Interferons; Interleukin-1; Interleukin-6; Intervention; Investigation; Lead; Life; Limbic System; Modeling; Mus; Neuraxis; Neuronal Dysfunction; Neurons; Oryctolagus cuniculus; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Plague; Prevention; Production; Public Health; Pyramidal Cells; Rattus; Recurrence; Refractory; Relative (related person); Reporting; Respiratory syncytial virus; Risk; Risk Factors; Role; Rotavirus; Route; Seizures; Staining and Labeling; Staining method; Stains; Structure; TMEV; Temporal Lobe Epilepsy; Testing; Tumor Necrosis Factor-alpha; Viral; Viral Antigens; Viral Encephalitis; Virus; Virus Diseases; cytokine; influenzavirus; killings; mouse model; mutant; neuron loss; neurotoxic; neurotropic; novel; novel strategies; novel therapeutic intervention; novel therapeutics; olfactory bulb; public health relevance; suicidal risk; virus host interaction

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.

描述（由申请人提供）：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危险因素。癫痫症的发病率约为 1% 至 3%，影响着大约 250 万美国人和全世界超过 5000 万个人。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。脑炎和由此造成的中枢神经系统损伤可以改变这些输入。感染引发的癫痫症通常对许多现有的抗癫痫药物无效。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疗法对于公众健康非常重要。 不同的病毒感染可引起脑炎，从而导致癫痫发作。这些病毒包括疱疹病毒，例如人类疱疹病毒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（肠道病毒 71）会引起脑炎，患者经常出现癫痫发作。困扰该领域的一个问题是，没有良好的实验动物模型来研究病毒脑炎如何导致癫痫。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。这些动物会患上急性脑炎并出现癫痫发作，但最终死于感染。泰勒氏鼠脑脊髓炎病毒 (TMEV) 是一种嗜神经小核糖核酸病毒。我们开发了一种新的模型，其中 C57BL/6 小鼠感染 TMEV 丹尼尔斯病毒 (DAV) 株会导致感染后第 3 天至第 10 天发生急性癫痫发作。小鼠康复，但经过一段可变的潜伏期后，小鼠开始自发性癫痫发作。这是第一个感染驱动的颞叶癫痫模型。我们建议在具体目标 1 中测试以下假设：海马锥体细胞的直接病毒感染会导致癫痫发作。在具体目标 2 中，我们假设 DAV 感染将细胞因子风暴瞄准中枢神经系统内的区域，从而导致神经元功能障碍和死亡。 相关性：病毒性脑炎幸存者中高达 20% 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。我们的病毒模型可能更相关，特别是对于使用抗炎方法测试新的治疗策略。如上所述，约 30% 的癫痫患者对现有的抗癫痫药物耐药，最近 FDA 建议对 11 种癫痫药物附加警告，揭示自杀风险。因此，有必要采取新的方法。 公共卫生相关性：中枢神经系统的病毒感染会导致脑炎。病毒性脑炎与癫痫发作和癫痫发作的风险增加有关。我们开发了一种新型病毒诱发癫痫小鼠模型。其他癫痫动物模型使用电刺激或神经毒性物质杀死和/或改变中枢神经系统内的神经元，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难以治疗，最近 FDA 建议对 11 种癫痫药物附加警告，揭示自杀风险。因此，需要针对这种疾病采取新的方法。