Immunotherapy Ameliorate Neurological Deficits in Encephalitis

描述（由申请人提供）：1型单纯疱疹病毒（HSV）感染在男性中普遍存在，全球85%的成年人处于潜伏感染状态。HSV脑炎（HSE）是最普遍的散发病毒性脑炎，由新生儿的原发性感染或成人的再激活潜伏感染引起。尽管HSE诊断的重大进展和强效抗病毒药物的开发显著降低了死亡率，但大多数幸存者（约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的长期损害通常局限于人类的边缘系统。小鼠鼻内接种在支持多种功能包括记忆、情感、行为和嗅觉的大脑边缘区域播下感染的种子。重要的是，边缘区域的炎症病变和长期炎症与未治疗的HSV感染存活小鼠的记忆障碍有关。因此，这种小鼠模型非常适合于探索可以改善大多数存活的HSE患者长期神经功能缺陷的治疗方法。我们已经明确地表明，HSE的病理基础是由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引起的。与仅阻断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）具有有效的抗炎和抗病毒作用，可预防HSE。我们提出对HSV脑感染存活小鼠进行神经行为测试，以验证特异性目的1中的假设，即与ACV单药治疗相比，联合抗病毒免疫治疗（ACV+IVIG）将减少HSV感染小鼠的中枢神经系统免疫病理，从而改善神经系统预后。在特异性目标2中，目标是使用血清蛋白质组学特征来鉴定分别接受ACV- ivig联合治疗或ACV单药治疗的感染小鼠中与有益抗炎反应和有害促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）将用于鉴定IVIG治疗小鼠中聚集在与抗炎反应相关的途径上的上调蛋白，从而代表候选生物标志物。经过进一步的测试和验证，这些生物标记物将在临床上用于预测理想的抗炎反应，而不是在使用含有IVIG作为抗炎和免疫调节药物的抗病毒免疫疗法鸡尾酒治疗的患者中出现不良的促炎反应。

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.