HSV/CYTOKINE INTERACTIONS IN THE NERVOUS SYSTEM

描述(申请人摘要)：消除嗜神经性病毒 例如来自神经系统的单纯疱疹病毒(HSV)很可能 复杂，并涉及除感染病毒的直接裂解之外的其他机制 细胞毒性T细胞(CTL)，因为MHC抗原不正常 在神经系统中表达。初步研究显示， 小鼠三叉神经炎性反应的广泛性和长期性 潜伏期的神经节(TG)和脑干。与以下各项相关的T细胞 分泌的干扰素-g集中在形态上看起来像是神经元周围。 正常，其中一些人潜伏感染了HSV。肿瘤坏死因子-α和白介素2 在潜伏期也检测到转录本。根据调查人员的说法 初步研究和已发表的其他研究，假设 干扰素-g和肿瘤坏死因子在抑制HSV复制中发挥重要作用 急性期有助于感染神经元的存活，而且它是 进一步推测，它们也可能起到调节频率的作用 可检测到的重新激活。在这项应用中，免疫-聚合酶链式反应分析将 用于确定HSV抗原是否在神经节和神经节中表达 潜伏期的大脑和这些组织中的细胞因子谱 用核糖核酸酶保护法测定。调查人员将确定 干扰素-g和肿瘤坏死因子-α在多大程度上协同控制单纯疱疹病毒复制 通过比较对照组神经系统感染病程、干扰素-g 野生型基因敲除(GKO)和肿瘤坏死因子受体基因敲除(TNFR1，2)小鼠 型单纯疱疹病毒，或表达干扰素-g转基因的单纯疱疹病毒重组体(HSV-g)。 表达干扰素-g受体的单纯疱疹病毒突变株(HSV-GR) 将用于干扰素-g受体基因敲除(RGKO)小鼠的研究 确定干扰素-g的作用是否通过与 感染神经元和其他细胞上的受体。干扰素-g的潜力 和肿瘤坏死因子来调节可检测到的HSV重新激活的频率一次 将在潜伏感染的RGKO小鼠、GKO小鼠和 对照组小鼠接种HSV-GR，并进行一过性感染 体温过低是一种再激活刺激。这里提出的研究旨在 加强对干扰素-g和肿瘤坏死因子α/b在肿瘤控制中的作用的认识 神经系统中的急性单纯疱疹病毒感染并阐明它们在 延迟。自从慢性干扰素-g分泌发作被证实以来 在HSV感染神经系统的过程中，HSV可能参与了多种 与细胞因子表达增加相关的神经系统疾病的研究 大脑。

DESCRIPTION (Applicant's abstract): The elimination of neurotropic viruses such as herpes simplex virus (HSV) from the nervous system is likely to be complex, and to involve other mechanisms besides direct lysis of infected cells by cytotoxic T cells (CTL) because MHC antigens are not normally expressed in the nervous system. Preliminary studies have revealed an extensive and prolonged inflammatory response in the mouse trigeminal ganglion (TG) and brain stem during latency. T cells associated with secreted IFN-g were focused around neurons that appeared morphologically normal, some of which were latently infected with HSV. TNF-a and IL-2 transcripts were also detected during latency. Based on the investigators preliminary studies and published studies of others, it is hypothesized that IFN-g and TNF play an important role in suppressing HSV replication at the acute stage contributing to the survival of infected neurons, and it is speculated further that they might also function to modulate the frequency of detectable reactivation. In this application an immune-PCR assay will be used to determine whether HSV antigens are expressed in the ganglion and brain during latency and the cytokine profile in these tissues will be determined by RNAse protection assay. The investigators will determine the extent to which IFN-g and TNF-a synergize to control HSV replication in the nervous system by comparing the course of infection in control, IFN-g knockout (gko) and TNF receptor knockout (TNFR1,2) mice inoculated with wild type HSV, or a HSV recombinant (HSV-g) that expresses an IFN-g transgene. An HSV mutant (HSV-gR) engineered to express the IFN-g receptor (IFN-gR) will be used in studies with IFN-g receptor knockout (Rgko) mice to determine whether the effects of IFN-g are mediated through interaction with the receptor on infected neurons and other cells. The potential of IFN-g and TNF to modulate the frequency of detectable HSV reactivation once initiated will be examined in latently infected Rgko mice, gko mice, and control mice inoculated with type HSV-gR, and subjected to transient hypothermia as a reactivation stimulus. Studies proposed here aim to enhance our understanding of the role of IFN-g and TNFa/b in the control of acute HSV infections in the nervous system and clarify their role in latency. Since episodes of chronic IFN-g secretion have been demonstrated during HSV infection in the nervous system, HSV may be involved in a variety of neurological disorders associated with increased cytokine expression in the brain.