Impact of metabolic regulation on viral neuro-virulence

摘要 病毒很少进入大脑，但当它们进入大脑时，其影响可能是毁灭性的。疱疹就是一个例子。 单纯脑炎(HSE)，成人罕见疾病，通常由1型单纯疱疹病毒(HSV-1)引起 最常见的是已经潜伏感染病毒的人。尽管出现了一些HSE病例 在有免疫系统遗传问题或严重免疫抑制的人中，受影响最大的 人们的免疫系统没有明显的问题。HSE为什么会发生在这些人身上的解释是 仍然需要。我们假设HSE发生在包括病毒重新激活在内的一系列事件中 从免疫系统的一个或多个组件受到损害时的延迟，可能 暂时的，由于某些新陈代谢功能的改变。这些想法不能在人体上进行测试，但我们已经 建立了一种可以评估导致HSE的事件的小鼠模型。因此，我们可以在一个 用2-脱氧葡萄糖分子局部抑制小鼠糖代谢模型的建立 HSV-1感染导致大多数动物发生HSE。我们计划对这些进行验证和扩展 初步发现并寻求对结果的机械解释。我们预计2DG 治疗可能会损害免疫防御的某些阶段，而免疫防御通常是防止中枢神经系统感染的。 神经系统。第一种是削弱一种或多种天然免疫成分的功能。 在感染部位，或在局部神经节内。这阻止了先天细胞的功能足以 限制局部病毒复制的程度，并最大限度地减少对局部神经节神经元的生产性感染。 第二个成分被认为是对CD8 T细胞的扩增或效应器功能的影响 正常情况下保护神经元，防止病毒在重新激活时潜伏传播到 大脑。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的诊断程序和治疗管理的变化。因此，除了当前使用的 抗病毒药物治疗任何检测到的代谢异常也可以通过联合使用来纠正 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.