CONTROL OF HSV IN THE PERIPHERAL NERVOUS SYSTEM

单纯疱疹病毒(HSV)是一种含有DNA的包膜病毒 是人类的天然病原体。在免疫功能正常的人中，HSV 口腔面部或泌尿生殖道粘膜上皮的感染 一般有限，表现为亚临床感染或 一种高度清晰的水泡性病变，愈合迅速。标志性的 然而，HSV感染的关键是它们进入感官的能力 周围神经系统(PNS)的神经元和建立潜伏期 感染。在大约30%的受感染的免疫活性 个体，HSV从潜伏状态重新激活，向下迁徙 轴突突起并重新引发复发的感染 感染的原始部位。产生这种变化的原因 人群中的复发感染尚不清楚，但可能 反映宿主免疫机制在控制病毒感染方面的效率 感染的初始阶段。单纯疱疹病毒感染可能是毁灭性的 免疫反应因以下原因而受损的个人 免疫抑制感染或肿瘤或免疫抑制 化疗。在这些个体中，单纯疱疹病毒可以传播， 累及中枢神经系统(CNS)，并可能导致死亡。 这种易感性的增加很可能反映了体内的功能障碍 免疫系统的T淋巴细胞室。然而，T细胞 损伤并不总是导致严重的播散性单纯疱疹病毒感染 在感染的、免疫抑制的个体中。一个关键因素可能是 宿主成功控制初始感染的能力。这个 成功地限制感染可能足以预防 随后复发的感染，即使在条件下 严重的免疫损伤。在这项提案中，一个定义明确的 将采用小鼠皮肤HSV感染模型作为对照 感染的效率很高，并且依赖于完整的T细胞 功能。T细胞亚群的解剖(S)负责和 限制HSV的机制可能会让我们洞察“最佳” 对这种病原体的反应。主要焦点将放在角色上 CD8 T细胞亚群和细胞因子干扰素-γ 控制皮肤和三叉神经节内的原发单纯疱疹病毒感染。在AIM 1、单纯疱疹病毒在这些地区的繁殖和传播特点 CD8 T细胞缺陷小鼠的两个感染部位将被确定。 足垫皮肤内达到的传染性单纯疱疹病毒水平 在单独的脊神经节节段内将进行评估。这个 感染后机体免疫功能表达与免疫功能的关系 组织和引流区域淋巴结与单纯疱疹病毒感染的局限性 将对皮肤和三叉神经痛进行评估。在目标2中，函数和 介导皮肤和皮肤病毒清除的CD8T细胞的特异性 将使用采用迁移模型对PNS进行调查。 具体地说，皮肤中干扰素-γ的相对贡献 PNS将通过对受体小鼠进行中和处理来评估 抗干扰素-γ抗体。在目标3中，干扰素-γ的重要性将 使用细胞因子的模型进行更详细的研究 在整个感染过程中不存在或被中和， 体内输注重组小鼠干扰素-γ(r-u-干扰素-γ)。 干扰素-γ可能介导其作用的潜在机制将是 调查过了。

Herpes simplex virus (HSV) is a DNA containing, enveloped virus that is a natural pathogen of humans. In immunocompetent individuals, HSV infections of the orofacial or genitourinary mucosal epithelia are generally limited, presenting as either a subclinical infection, or as a highly defined vesicular lesion which heals rapidly. The hallmark of HSV infections, however, is their ability to enter the sensory neurons of the peripheral nervous system (PNS) and establish a latent infection. In approximately 30% of infected immunocompetent individuals, HSV reactivates from the latent state, migrate back down the axonal processes and reinitiate a recrudescent infection at the original site of infection. The reasons for the variability of recrudescent infection within the population is not known, but may reflect the efficiency of the host immune mechanisms in controlling the initial phase of infection. HSV infections may be devastating in individuals whose immune responses are impaired due to immunosuppressive infections or neoplasias or immunosuppressive chemotherapeutic treatment. In these individuals, HSV may disseminate, involve the central nervous system (CNS), and possibly cause death. This increased susceptibility is likely to reflect dysfunction within the T lymphocyte compartment of the immune system. However, T cell impairment does not always result in severe, disseminated HSV infection in infected, immunosuppressed individuals. A critical factor may be the ability of the host to successfully control initial infection. The successful limitation of infection may be sufficient to prevent subsequent episodes of recrudescent infection, even under conditions of severe immunological impairment. In this proposal, a well defined murine model of cutaneous HSV infection will be used in which control of infection is highly efficient and dependent upon intact T cell function. The dissection of the T cell subset(s) responsible and the mechanisms by which HSV is limited may give insight into the "optimal" response to this pathogen. The principal focus will be upon the role of the CD8 T cell subset and the cytokine interferon-gamma (IFN-gamma) in controlling primary HSV infection within skin and the PNS. In Aim 1, the characteristics of HSV multiplication and spread within these two sites of infection will be determined in CD8 T cell-deficient mice. The levels of infectious HSV attained within the skin of the footpad and within individual spinal ganglia segments will be assessed. The relationship between the expression of immune functions within infected tissues and the draining regional lymph node and the limitation of HSV in skin and PNS will be assessed. In Aim 2, the function and specificity of CD8 T cells which mediate viral clearance in skin and PNS will be investigated using an adoptive transfer model. Specifically, the relative contribution of IFN-gamma within the skin and PNS will be assessed by treating recipient mice with neutralizing anti-IFN-gamma antibody. In Aim 3, the importance of IFN-gamma will be more investigated in more detail using models in which the cytokine is absent or neutralized throughout the course of infection and by the infusion of recombinant murine IFN-gamma (r-mu-IFN-gamma) in vivo. Potential mechanisms by which IFN-gamma may mediate its effect will be investigated.