Immunotherapy Ameliorate Neurological Deficits in Encephalitis

免疫疗法可改善脑炎的神经功能缺陷

• 批准号: 8771312
• 负责人: EDOUARD M CANTIN
• 金额: $ 25.38万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771312
• 关键词: Acute; Acyclovir; Adult; Affect; Affinity; Aftercare; Alzheimer' s Disease; Amygdaloid structure; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Antiviral Therapy; Area; Behavior; Bioinformatics; Biological; Biological Markers; Brain; Brain region; Caring; Cell Nucleus; Central Nervous System Infections; Child; Clinical; Cognitive; Combined Modality Therapy; Cytopathology; Data; Development; Diagnosis; Diagnostic Procedure; Disease; Emotions; Encephalitis; Goals; Herpesvirus 1; Human; Hypothalamic structure; Immunotherapeutic agent; Immunotherapy; Impairment; Incidence; Independent Living; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Intravenous Immunoglobulins; Latent Virus; Learning Disabilities; Lesion; Licensing; Limbic System; Medial; Memory; Memory impairment; Modeling; Motor; Mus; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurological outcome; Neurological status; Neurons; Newborn Infant; Outcome; Pathology; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Preparation; Proteins; Proteomics; Reproducibility; Resolution; Risk; Risk Factors; Route; Running; Sampling; Seeds; Sensory; Serum; Serum Proteins; Simplexvirus; Smell Perception; Specificity; Survivors; Temporal Lobe; Testing; Thalamic structure; Time; Trigeminal System; Trigeminal nerve structure; Validation; Viral Encephalitis; Viral load measurement; Virus; West Nile virus; clinical efficacy; combinatorial; disability; expectation; immunopathology; improved; latent infection; man; mortality; mouse model; neonate; neurobehavioral test; olfactory bulb; permissiveness; piriform cortex; prevent; public health relevance; response

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.

描述（由申请人提供）：1型单纯疱疹病毒（HSV）感染在人类中普遍存在，全球成年人群中有>85%的人潜伏感染。HSV脑炎（HSE）是最常见的散发性病毒性脑炎，由新生儿原发感染或成人再激活的潜伏感染引起。虽然HSE诊断的重大进展和有效抗病毒药物的开发显着降低了死亡率，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;发展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）的同一边缘脑区域引发感染。重要的是，边缘区的炎性病变和长期炎症与HSV感染后存活的未治疗小鼠的记忆障碍相关。因此，这种小鼠模型非常适合探索可以改善大多数HSE患者长期神经功能缺损的治疗方法。我们已经明确表明，HSE的病理基础是夸大的CNS炎症反应，而不是病毒诱导的细胞病理学。与只阻断HSV复制的抗病毒药物阿昔洛韦相反，静脉注射免疫球蛋白（IVIG）发挥有效的抗炎和抗病毒作用来预防HSE。我们建议对HSV脑感染存活的小鼠进行神经行为测试，以验证特定目标1中的假设，即与ACV单药治疗相比，组合抗病毒免疫治疗（ACV+IVIG）将减少CNS免疫病理学，从而改善HSV感染小鼠的神经功能结局。在具体目标2中，目标是使用血清蛋白质组学谱来鉴定与分别接受组合ACV-IVIG或ACV单药治疗的感染小鼠中的有益抗炎反应相比有害促炎反应相关的蛋白质特征。生物信息学、统计学和免疫途径分析（IPA）将用于鉴定IVIG处理小鼠中上调的蛋白质，这些蛋白质汇聚在抗炎反应相关途径上，因此代表候选生物标志物。在进一步测试和验证后，这些生物标志物将在临床上用于预测所需的抗炎，与用掺入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中的不期望的促炎反应相比。