CONTROL OF HSV IN THE PERIPHERAL NERVOUS SYSTEM

HSV 对周围神经系统的控制

• 批准号: 2037743
• 负责人: STEPHEN ROBERT JENNINGS
• 金额: $ 14.39万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2037743
• 关键词: athymic mouse; cell mediated cytotoxicity; cellular immunity; cytotoxic T lymphocyte; disease /disorder model; gene expression; genetically modified animals; herpes simplex virus 1; host organism interaction; immunocytochemistry; interferon gamma; laboratory mouse; latent virus infection; nervous system infection; neuroimmunomodulation; neurotropic virus; neutralizing antibody; nitric oxide synthase; passive immunization; peripheral nervous system; polymerase chain reaction; skin infection; spinal ganglion; tissue /cell culture; virus replication

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.

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 在免疫功能正常的个体中，HSV 口面或泌尿生殖道粘膜上皮的感染是 一般有限，表现为亚临床感染，或 一种能迅速愈合的高度明确的水泡状损伤。 的标志 然而，HSV感染的主要原因是它们能够进入感觉器官， 周围神经系统（PNS）的神经元，并建立一个潜在的 感染 在大约30%的感染免疫活性 个体，HSV从潜伏状态重新激活， 轴突突起，并重新启动复发感染， 感染的原始部位。 变化的原因 人群中的复发感染尚不清楚，但可能 反映了宿主免疫机制在控制 感染的初始阶段。 HSV感染可能是毁灭性的， 免疫应答受损的个体， 免疫抑制性感染或肿瘤或免疫抑制性 化疗 在这些个体中，HSV可以传播， 涉及中枢神经系统（CNS），并可能导致死亡。 这种易感性的增加可能反映了体内的功能障碍 免疫系统的T淋巴细胞区室。 然而，T细胞 损伤并不总是导致严重的、播散性HSV感染 感染的免疫抑制的个体。 一个关键因素可能是 宿主成功控制初始感染的能力。 的 成功限制感染可能足以防止 即使在某些条件下， 严重的免疫缺陷 在这一建议中，一个明确的 将使用皮肤HSV感染的鼠模型，其中对照 感染的效率很高，依赖于完整的T细胞 功能 负责的T细胞亚群的解剖和 限制HSV的机制可能会让我们深入了解“最佳” 对这种病原体的反应 主要重点将放在 CD 8 T细胞亚群和细胞因子干扰素-γ（IFN-γ） 控制皮肤和PNS内的原发性HSV感染。 在Aim中 1、HSV的繁殖和传播特点在这些 将在CD 8 T细胞缺陷小鼠中确定两个感染位点。 足垫皮肤内达到的感染性HSV水平 和在单个脊神经节段内的神经节的数目。 的 感染者体内免疫功能表达的关系 组织和引流区域淋巴结以及HSV的局限性 将评估皮肤和PNS。 在目标2中，函数和 介导皮肤中病毒清除的CD 8 T细胞的特异性， 将使用过继转移模型研究PNS。 具体来说，皮肤内IFN-γ的相对贡献 和PNS将通过用中和性抗肿瘤药物治疗受体小鼠来评估。 抗IFN-γ抗体。 在目标3中，IFN-γ的重要性将 使用模型进行更详细的研究，其中细胞因子 在整个感染过程中， 体内输注重组鼠IFN-γ（r-mu-IFN-γ）。 IFN-γ可能介导其作用的潜在机制如下： 研究了