Impact of metabolic regulation on viral neuro-virulence

摘要 病毒很少进入大脑，但一旦进入，其影响可能是毁灭性的。一个例子是疱疹 单纯性脑炎（HSE），一种罕见的疾病，通常由单纯疱疹病毒1型（HSV-1）引起的成人 最常见于已经潜伏感染病毒的人。虽然一些HSE案例发生 在免疫系统有遗传问题或严重免疫抑制的人中， 人们的免疫系统没有明显的问题。解释为什么HSE发生在这样的人是 仍然需要。我们假设HSE发生在一系列事件的合并过程中，其中包括病毒的重新激活 当免疫系统的一个或多个组成部分受到损害时， 暂时性地，通过某些代谢功能的改变。这些想法无法在人类身上进行测试，但我们有 建立了一个小鼠模型，其中导致HSE的事件可以被评估。因此，我们可以在一个 2-脱氧葡萄糖抑制小鼠糖代谢模型 HSV-1感染导致大多数动物发生HSE。我们计划验证并扩展这些 初步的发现和寻找一个机制的解释结果。我们预计2DG 治疗可能会损害某些阶段的免疫防御，通常保护免受感染的中央 神经系统第一种被认为是一种或多种先天免疫成分功能的钝化 在感染部位或局部神经节内。这会阻止先天细胞充分发挥作用， 限制局部病毒复制的程度，并且还使局部神经节中神经元的生产性感染最小化。 第二种成分被认为是对CD 8 T细胞的扩增或效应功能的影响， 正常情况下保护神经元，并防止病毒在潜伏期重新激活后传播到神经元。 个脑袋该提案旨在检验我们的指导性假设。我们预计，我们的发现可能会导致 HSE诊断程序和治疗管理的变化。因此，除了目前使用的 抗病毒药物治疗任何检测到的代谢异常也可以得到纠正， 最大限度地减少HSE综合征后果的治疗策略。

Abstract Viruses rarely enter the brain but when they do, the effects can be devastating. An example is Herpes Simplex encephalitis (HSE), a rare disease in adults usually caused by Herpes Simplex virus type 1 (HSV-1) occurring most commonly in persons already latently infected with the virus. Although some cases of HSE occur in persons with genetic problems of the immune system or are heavily immunosuppressed, most affected persons have no overt problem with their immune systems. An explanation why HSE occurs in such persons is still needed. We hypothesize that HSE occurs during a coalescence of events, which included viral reactivation from latency at a time when one or more components of the immune system is being compromised, perhaps temporarily, by a change in some metabolic function. These ideas cannot be tested in humans but we have established a mouse model in which events leading up to HSE can be evaluated. Thus we could show in a mouse model that inhibition of glucose metabolism with the molecule 2-deoxyglucosue from the time of local infection with HSV-1 resulted in the majority of animals developing HSE. We plan to verify and extend these preliminary findings and search for a mechanistic explanation for the outcome. We anticipate that the 2DG therapy could impair some stages of immune defense, which normally protect against infection of the central nervous system. The first is proposed to be a blunting of the function of one or more innate immune components at the infection site, or within the local nerve ganglion. This prevents innate cells from functioning sufficiently to limit the extent of local viral replication and also minimizes productive infection of neurons in the local ganglion. The second component is proposed to be an effect on the expansion or effector function of CD8 T cells which in normal circumstances protect neurons and prevents virus upon reactivation from latency from spreading to the brain. The proposal is designed to test our guiding hypotheses. We anticipate that our findings could result in changes in diagnostic procedures and therapeutic management of HSE. Thus, in addition to the currently used antiviral drug treatment any detected metabolic abnormalities could be corrected as well, with the combination therapy strategy minimizing the consequences of the HSE syndrome.