The Neuroimmunology of Viral Infection

描述(申请人提供)：单纯疱疹病毒1型(HSV-1)是人类最常见的嗜神经性病原体之一，其血清阳性率在50岁时增加到60-80%。与HSV-1相关的临床疾病包括疱疹间质角膜炎，这是工业化世界中感染性角膜失明的主要原因，以及坦率的散发性脑炎，这是一种罕见但会导致死亡的疾病。对感染的抵抗力包括先天性免疫系统。对病毒感染的先天免疫反应的核心是I型干扰素途径，它被包括模式识别受体在内的各种手段激活后，导致有效的抗病毒途径的表达，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(外周和中枢)病毒感染与I型干扰素系统在局部宿主抵抗和随后对侮辱的适应性免疫反应中所起的作用之间的关系。缺乏I型干扰素功能途径的小鼠(即缺乏I型干扰素受体的阿尔法链，CD118-/-)被发现对HSV-1高度敏感，在感染后6天内，周围和中枢神经系统中的病毒滴度会升高。此外，随着T细胞凋亡和坏死的增加，引流淋巴结内的细胞大量丢失。CD118-/-小鼠感染后，神经系统内白细胞的募集也有明显变化。白细胞向神经系统募集的变化反映在感染组织中选定的趋化因子包括CXCL1、CXCL10和CCL2的特定变化。然而，驻留细胞(包括星形胶质细胞和小胶质细胞)与神经系统或有组织的淋巴组织(即引流的淋巴组织)内渗透的白细胞群体在I型干扰素途径对感染以及随后的获得性免疫反应和神经病理学的反应中的作用尚未被探索。我们建议使用缺乏选择基因的小鼠和小鼠嵌合体来解决这个问题。初步的、未发表的数据表明，驻留在脑干中具有完整的I型干扰素系统的驻留细胞对控制病毒感染至关重要，而在周围神经系统(即三叉神经节)或角膜中，具有I型干扰素途径的驻留细胞和骨髓来源的细胞都需要最大限度地抵抗感染。我们在这次竞争性更新中提出了两个具体目标。第一个目标将检验具有I型干扰素受体功能的小胶质细胞在眼睛感染后保持对HSV-1的抵抗力的假设。第二个目标将检验这样一个假设，即甘油三酯、角膜和引流淋巴结内具有I型干扰素受体的白细胞和驻留细胞都需要最大限度地抵抗HSV-1感染。预计该项目的结果将确定中枢神经系统和外周组织(包括感觉神经节和角膜)内先天和获得性免疫的关键核心成分，这些成分对于每个组织独特的病毒监测至关重要。在这样做的时候，专注于开发利用(通过扩增或激活)这些成分的疫苗，将比目前利用病毒编码蛋白的策略提供更好的疗效，目前的策略通常只产生抗体产生或T效应细胞的免疫反应。或者，神经发病机制的介体可以作为目标，以减轻侧枝损伤，从而保护患有急性或复发性HSV-1中枢神经系统或周围神经感染的患者的神经元。

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.