Immunotherapy Ameliorate Neurological Deficits in Encephalitis

描述(由申请人提供)：单纯疱疹病毒1型(HSV)感染在全球85%的成年人口中普遍存在。单纯疱疹病毒脑炎(HSV encenalitis，HSE)是一种最常见的散发性病毒性脑炎，由新生儿原发感染或成人潜伏感染复发引起。尽管HSE诊断的重大进展和有效抗病毒药物的开发大大降低了死亡率，但大多数幸存者(60%)患有严重的神经系统并发症，使他们无法恢复独立生活；患有认知和学习障碍的儿童的前景尤其黯淡。从解剖学和功能上讲，HSE造成的长期损害通常局限于人类的边缘系统。鼻腔接种小鼠种子感染同一边缘大脑区域，支持包括记忆、情感、行为和嗅觉在内的各种功能。重要的是，在HSV感染后存活的未经治疗的小鼠，边缘区域的炎性损伤和持续的炎症与记忆障碍有关。因此，这种小鼠模型非常适合于探索可以改善长期困扰大多数HSE患者的神经缺陷的治疗方法。我们已经明确地表明，HSE背后的病理基础是夸大的中枢神经系统炎症反应，而不是病毒诱导的细胞病理学。与只能阻断HSV复制的抗病毒药物阿昔洛韦不同，静脉注射免疫球蛋白(IVIG)具有强大的抗炎和抗病毒作用，可以预防HSE。我们建议对在HSV脑感染中存活的小鼠进行神经行为测试，以验证特定目标1的假设，即联合抗病毒免疫疗法(ACV+IVIG)与ACV单一疗法相比，将减少中枢神经系统免疫病理，从而改善HSV感染小鼠的神经预后。在特定的目标2中，目标是使用血清蛋白质组学特征来识别与分别接受ACV-IVIG或ACV单一治疗的感染小鼠的有害促炎反应相比，有益的抗炎反应相关的蛋白质特征。生物信息学、统计学和独创性途径分析(IPA)将被用于识别在静脉注射免疫球蛋白治疗的小鼠中上调的蛋白质，这些蛋白质聚集在与抗炎反应有关的途径(S)上，从而代表候选生物标志物。在进一步的测试和验证后，这些生物标志物将在临床上用于预测理想的抗炎反应，而不是使用包含IVIG作为抗炎和免疫调节药物的抗病毒免疫治疗鸡尾酒治疗的患者的不良促炎反应。

DESCRIPTION (provided by applicant): Herpes Simplex Virus type 1 (HSV) infections are ubiquitous in man with >85% of the global adult population being latently infected. HSV encephalitis (HSE) is the most prevalent sporadic viral encephalitis resulting from primary infections in neonates or reactivated latent infections in adults. Although, significant advances i diagnosis of HSE and development of potent antiviral drugs have significantly reduced mortality, most survivors (>60%) suffer severe neurological complications that preclude them returning to independent living; prospects for children who develop cognitive and learning disabilities are particularly bleak. Anatomically and functionally long-term damage from HSE is usually confined to the limbic system in man. Intranasal inoculation of mice seeds infection in this same limbic brain region that supports a variety of functions including memory, emotion, behavior and olfaction. Importantly, inflammatory lesions and prolonged inflammation in the limbic region has been correlated with memory impairment in untreated mice surviving HSV infection. Thus this mouse model is ideally suited for exploring treatments that could ameliorate long-term neurological deficits afflicting most patients surviving HSE. We have shown definitively that the pathology underlying HSE results from exaggerated CNS inflammatory responses rather than virus-induced cytopathology. In contrast to the antiviral drug acyclovir, that blocks only HSV replication, intravenous immunoglobulins (IVIG) exert potent anti-inflammatory and antiviral effects to prevent HSE. We propose neurobehavioral testing of mice surviving HSV brain infection to validate the hypothesis in Specific Aim 1 that combinatorial antiviral-immunotherapy (ACV+IVIG), compared ACV monotherapy, will reduce CNS immunopathology and thereby result in improved neurological outcomes for HSV infected mice. In Specific Aim 2, the goal is to use serum proteomic profiles to identify protein signatures that are correlated with beneficial anti-inflammatory responses compared to deleterious proinflammatory responses in infected mice receiving combinatorial ACV-IVIG or ACV monotherapy, respectively. Bioinformatic, statistical and Ingenuity Pathway Analysis (IPA) will be used to identify proteins upregulated in IVIG treated mice that converge on pathway(s) implicated in anti-inflammatory responses and thus represent candidate biomarkers. After further testing and validation these biomarkers would be clinically useful for predicting desirable anti-inflammatory, as compared to undesirable proinflammatory responses in patients treated with an antiviral-immunotherapy cocktail incorporating IVIG as an anti-inflammatory and immunomodulatory drug.