The Neuroimmunology of Viral Infection

病毒感染的神经免疫学

• 批准号: 8870272
• 负责人: DANIEL J CARR
• 金额: $ 36.79万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870272
• 关键词: Acute; Address; Animals; Antibody Formation; Apoptosis; Astrocytes; Biological Preservation; Blindness; Bone Marrow; Brain Stem; CCL2 gene; CXCL1 gene; CXCL10 gene; Cells; Cessation of life; Chimera organism; Clinical; Cornea; Data; Development; Disease; Effector Cell; Encephalitis; Epithelium; Eye Infections; Fiber; Genes; Herpesvirus 1; Herpetic Keratitis; Host resistance; Human; Immune response; Immune system; Immunohistochemistry; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory Response; Interferon Type I; Lead; Leukocytes; Life; Lymphoid Tissue; Magnetic Resonance Imaging; Mediator of activation protein; Microglia; Molecular; Mus; Natural Immunity; Necrosis; Nervous system structure; Neuraxis; Neurons; Neuropathogenesis; Outcome; Outcome Study; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Peripheral; Peripheral Nerves; Peripheral Nervous System; Population; Proteins; Recurrence; Relative (related person); Resistance; Resistance to infection; Role; Sensory; Sensory Ganglia; Seroprevalences; Severities; Structure of trigeminal ganglion; System; T-Lymphocyte; Techniques; Testing; Tissues; Toll-like receptors; Viral; Viral Load result; Virion; Virus; Virus Diseases; Virus Replication; adaptive immunity; anterograde transport; base; chemokine; comparative efficacy; defined contribution; lymph nodes; neuroimmunology; neuroinflammation; neuropathology; neurotropic; novel; pathogen; response; type I interferon receptor; vaccine development

DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) is one of the most common neurotropic pathogens in humans with a seroprevalence rate increasing up to 60-80% by the 5th decade of life. Clinical diseases associated with HSV-1 include herpetic stromal keratits, the leading cause of infectious corneal blindness in the industrialized world, and frank sporadic encephalitis, a rare but debilitating disease that can result in death. Resistance to infection includes the innate immune system. Central to the innate immune response to virus infection is the type I interferon (IFN) pathway which upon activation by a variety of means including pattern recognition receptors results in the expression of potent anti-viral pathways that block virus replication at the transcriptional and translational levels. Recently, we have begun to explore the relationship between virus infection in the nervous system (peripheral and central) and the role of the type I IFN system in local host resistance and the ensuing adaptive immune response to the insult. Mice deficient in a functional type I IFN pathway (i.e., absence of the alpha chain of the type I IFN receptor, CD118-/-) are found to be highly sensitive to HSV-1 succumbing to infection within 6 days associated with an elevation in virus titer in the peripheral and central nervous systems. Moreover, there is a massive loss of cells residing in the draining lymph node associated with an increase in T cell apoptosis and necrosis. There are also notable changes in recruitment of leukocytes residing in the nervous system post infection of CD118-/- mice. Changes in leukocyte recruitment to the nervous system are reflected by specific changes in select chemokines including CXCL1, CXCL10 and CCL2 in the infected tissue. However, the contribution of resident cells (including astrocytes and microglia) versus infiltrating leukocyte populations within the nervous system or the organized lymphoid tissue (i.e., draining lymph node) in the context of a functional type I IFN pathway in response to infection and the ensuing adaptive immune response and neuropathology is unexplored. We propose to employ mice deficient in select genes as well as mouse chimeras to address this question. Preliminary, unpublished data suggest the resident cells residing in the brain stem with an intact type I IFN system are critical to control viral infection whereas in the peripheral nervous system (i.e., trigeminal ganglion) or cornea, both resident and bone marrow-derived cells with a functional type I IFN pathway are required to maximize resistance to infection. We propose two specific aims within this competitive renewal. The first aim will test the hypothesis microglia with a functional type I IFN receptor maintain resistance to HSV-1 following ocular infection. The second aim will test the hypothesis that both leukocytes and resident cells within the TG, cornea, and draining lymph node with a functional type I IFN receptor are required to maximize resistance to HSV-1 infection. It is anticipated the outcome of this project will identify key central components of innate and adaptive immunity within the CNS and peripheral tissues (including sensory ganglia and cornea) that are critical for viral surveillance unique to each tissue. In so doing, a focus on the development of vaccines that utilize (via expansion or activation) such components will provide superior efficacy compared to current strategies that utilize viral encoded proteins that typically generate an immune response incorporating only antibody production or T effector cells. Alternatively, mediators of neuropathogenesis can be targeted to alleviate collateral damage and thus, preservation of neurons in patients that suffer from acute or recurrent HSV-1 CNS or peripheral nerve infection.

描述（由申请人提供）：单纯疱疹病毒1型（HSV-1）是人类中最常见的神经智病病原体之一，到期5年的5个十年，血清阳性率提高了60-80％。与HSV-1相关的临床疾病包括疱疹性基质角化膜，工业化世界中传染性角膜失明的主要原因以及弗兰克散发性脑炎，这是一种罕见但令人衰弱的疾病，可能导致死亡。对感染的抵抗包括先天免疫系统。对病毒感染的先天免疫反应的核心是I型干扰素（IFN）途径，在通过多种手段（包括模式识别受体）激活后，它会导致有效的抗病毒途径表达，该途径在转录和翻译水平上阻止病毒复制。最近，我们已经开始探索神经系统（外围和中心）中病毒感染与I型IFN系统在局部宿主抗性中的作用与随之而来的适应性免疫反应对损害的关系。发现缺乏功能性I型IFN途径的小鼠（即缺乏I型IFN受体的α链，CD118 - / - ）对HSV-1高度敏感，在6天内屈服于感染，与外围和中枢神经系统中病毒滴度的高度相关。此外，与T细胞细胞凋亡和坏死有关的排水淋巴结中存在大量细胞损失。 CD118 - / - 小鼠感染后居住在神经系统中的白细胞的募集也有明显的变化。神经系统募集的白细胞募集的变化反映在被感染组织中的CXCL1，CXCL10和CCL2（包括CXCL1，CXCL10和CCL2）中的特定变化反映。但是，在神经系统或有组织的淋巴组织组织中，居民细胞（包括星形胶质细胞和小胶质细胞）与浸润白细胞种群的贡献（即，在功能性I型IFN途径响应感染和随后的适应性不合毒剂的反应和肿瘤学的情况下，在功能上I型途径中的有组织的淋巴组织（即排干淋巴结）的贡献。我们建议使用缺乏精选基因的小鼠以及小鼠嵌合体来解决这个问题。初步未发表的数据表明，驻留在脑干中的驻留细胞具有完整的I型IFN系统对于控制病毒感染至关重要，而在外周神经系统（即三叉神经节）或角膜中，驻留和骨髓骨髓的细胞都需要具有功能性的I IFN途径，以最大程度地抗性。我们在此竞争更新中提出了两个具体目标。第一个目标将用功能性I型IFN受体在眼部感染后对HSV-1保持抗性测试假设小胶质细胞。第二个目的将检验以下假设：TG，角膜和排水淋巴结内的白细胞和驻留细胞具有功能性I型IFN受体，以最大程度地提高对HSV-1感染的抗性。预计该项目的结果将确定中枢神经系统和周围组织（包括感觉神经节和角膜）内的先天和适应性免疫力的关键中心成分，这对于每种组织独有的病毒监测至关重要。这样一来，与当前利用病毒编码蛋白的策略相比，使用（通过扩展或激活）使用（通过扩展或激活）的疫苗开发将提供较高的功效，这些策略通常会产生仅结合抗体产生或T效应细胞的免疫反应。或者，神经病发生的介体可以针对减轻副作用损害，因此可以保存患有急性或复发性HSV-1 CNS或周围神经感染的患者的神经元。