Herpes Simplex Virus, Early Brain Injury and Epilepsy

描述（由申请人提供）：1型单纯疱疹病毒（HSV-1）是人类急性和复发性疾病的常见原因。初次感染后，通常发生在儿童时期，1型单纯疱疹病毒在神经系统中处于休眠状态。本研究旨在探索一种新的假说，即早期感染HSV-1在颞叶癫痫（TLE）的发生中起关键作用。这种病毒可能通过创造一种特殊的大脑焦点，涉及神经回路的改变和独特的胶质/微血管基质的形成，从而促进癫痫发生和癫痫发作的维持。一些观察结果表明，1型单纯疱疹病毒可能导致TLE。例如，1型单纯疱疹病毒脑炎的幸存者经常发展为癫痫。HSV-1在引起脑炎时，优先侵入和损害包括海马在内的边缘结构，这在TLE中也表现出神经病理改变。此外，难治性TLE患者的海马潜伏性HSV-1感染率比对照组高10倍。为了评估我们的假设，提出了两种方法。(1)通过评估手术切除的TLE患者海马中病毒DNA（通过聚合酶链反应）和病毒粒子（通过免疫组织化学）的存在，批判性地探索HSV-1与TLE之间的联系，并将它们与TLE的特定神经病理特征(即(a)门门间神经元丢失，（b)胶质瘤形成和(c)血管增殖）联系起来。(2)为了评估HSV-1与TLE慢性癫痫发作和神经病理发展的因果关系，将研究HSV-1感染大鼠模型，并评估感染的实验修饰因子，如(a)病毒株，(b)年龄，(c)发热/热性癫痫发作，(d)急性癫痫发作。通过研究感染期间病毒入侵的模式和时间过程，探索病毒诱导的神经病理和癫痫发作的细胞/分子机制。如果病毒引起的TLE被确定，那么这不仅将为预防和控制这种疾病开辟新的途径，而且还将提高我们对病毒引起的脑损伤的理解。

DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) is a common cause of acute and recurrent disease in humans. After the primary infection, which usually occurs in childhood, HSV-1 remains dormant in the nervous system. This proposal is aimed at exploring a novel hypothesis that early infection with HSV-1 plays a critical role in the genesis of temporal lobe epilepsy (TLE). The virus may contribute to this by creating a specialized brain focus involving alterations in neural circuitry and formation of a unique glial/microvascular substrate that promotes epileptogenesis and maintenance of seizures. Several observations suggest that HSV-1 may cause TLE. For example, survivors of HSV-1 encephalitis frequently develop epilepsy. HSV-1, when causing encephalitis, preferentially invades and lesions limbic structures, including the hippocampus, which also shows neuropathological changes in TLE. Moreover, patients with medically intractable TLE have a ten times higher rate of latent HSV-1 infection in their hippocampus than control subjects. To evaluate our hypothesis two approaches are proposed. (1) To critically explore the connection between HSV-1 and TLE by assessing the presence of viral DNA (by polymerase chain reaction) and virions (by immunohistochemistry) in surgically resected hippocampi from TLE patients, and correlating these with the specific neuropathological characteristics of TLE, i.e. (a) loss of hilar interneurons, (b) gliosis, and (c) vascular proliferation. (2) To assess the causal relationship of HSV-1 to the development of chronic seizures and neuropathology in TLE, rat models of HSV-1 infection will be studied and experimental modifiers of infection such as (a) viral strain, (b) age, (c) fever/febrile seizures, and (d) acute seizures, will be evaluated. The cellular/molecular mechanisms of viral-induced neuropathology and seizures will be explored by investigating the pattern and time-course of viral invasion during the infection. If a viral causation of TLE is established, then this would not only open new avenues for prevention and control of this disorder, but also improve our understanding of viral-induced brain injury.