HSV/CYTOKINE INTERACTIONS IN THE NERVOUS SYSTEM

描述（申请人摘要）：嗜神经病毒的消除 如单纯疱疹病毒（HSV）从神经系统很可能是 复杂，并涉及其他机制，除了直接裂解感染 细胞毒性T细胞（CTL），因为MHC抗原通常不 在神经系统中表达。 初步研究显示， 在小鼠三叉神经中广泛和延长的炎症反应 神经节（TG）和脑干在潜伏期。 T细胞与 分泌的IFN-g集中在形态学上出现的神经元周围 正常，其中一些潜伏感染HSV。 TNF-a和IL-2 在潜伏期也检测到转录本。 根据研究者 初步研究和其他人发表的研究，据推测， IFN-g和TNF在抑制HSV复制中起重要作用， 急性期有助于受感染神经元的存活， 进一步推测，它们也可能起到调制频率的作用， 可以检测到的重新激活 在该应用中，免疫PCR测定将是 用于确定HSV抗原是否在神经节中表达， 在潜伏期和这些组织中的细胞因子谱将被 通过RNA酶保护测定确定。 调查人员将确定 IFN-γ和TNF-α协同作用控制HSV复制的程度 神经系统通过比较对照组的感染过程， gko和TNF受体敲除（TNFR 1，2）小鼠接种野生型 型HSV或表达IFN-g转基因的HSV重组体（HSV-g）。 经工程改造以表达IFN-g受体（IFN-gR）的HSV突变体（HSV-gR） 将用于IFN-g受体敲除（Rgko）小鼠的研究， 确定IFN-g的作用是否通过与 受感染的神经元和其他细胞上的受体。 IFN-g的潜力 和TNF来调节可检测的HSV再激活的频率， 将在潜伏感染的Rgko小鼠、gko小鼠和 对照小鼠接种HSV-gR型，并进行短暂的 低温作为激活刺激。 本文提出的研究旨在 增强我们对IFN-g和TNFa/B在控制 急性HSV感染的神经系统，并阐明其作用， 延迟。 由于慢性IFN-γ分泌的发作已被证明 在神经系统中HSV感染期间，HSV可能参与多种 与细胞因子表达增加相关的神经系统疾病 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.