IMMUNOBIOLOGY OF VARICELLA AND ZOSTER IN A PRIMATE MODEL

原发性水痘带状疱疹病毒（VZV）感染产生水痘（水痘），之后病毒变成 潜伏在神经节中的重新激活产生带状疱疹。带状疱疹的神经系统并发症是 在对VZV的细胞介导的免疫力降低的老龄人群中增加。在水痘期间， 病毒通过血源性传播或通过从感染的皮肤逆行轴突运输进入神经节， 扁桃体记忆性CD4+ T细胞。VZV特异性T细胞对于维持神经节中的潜伏期不是必需的。 病毒的潜伏期和再活化可能是由涉及细胞因子的先天性免疫反应或 趋化因子我们开发了一种与人类VZV感染相似的实验动物模型。 灵长类动物自然感染猴水痘病毒（SW）导致神经节潜伏期和再激活 经过放射治疗和免疫抑制药物治疗后。软件的重新激活伴随着 细胞因子水平的变化和神经节中神经元附近的T细胞簇的出现， 重新激活的病毒这些数据为我们的假设提供了理论基础，即免疫细胞和 非免疫细胞以及由这些细胞在它们与 神经元是原发性水痘病程、潜伏期和再激活的重要决定因素。 为了确定SW感染皮肤和感觉神经节的途径，我们将鉴定宿主细胞类型 以及它们在皮肤和神经节中SW感染的运输和建立中的作用。 感染（目标1）。因为，神经节中的SW潜伏期和再激活更可能由神经元调节。 涉及细胞因子的先天性免疫应答，我们将比较潜伏期期间细胞因子的表达， 和猴神经节中的再激活（Aim 2）。确定神经节中SW特异性T细胞应答 在再激活过程中，我们将鉴定浸润神经节的T细胞的表型和特异性。 在软件重新激活期间（目标3）。全面了解细胞类型和免疫学 影响SW从原发感染部位转运至皮肤和感觉神经节的因素 沿着对潜伏期期间神经节中局部SVV特异性T细胞应答的理解， 重新激活将确定预防人类带状疱疹的潜在靶点。后者尤其 在迅速增加的老年人和免疫功能低下人群中的重要性， VZV再激活会导致慢性的、有时是致命的神经系统疾病。

Primary varicella zoster virus (VZV)infection produces chickenpox (varicella), after which virus becomes latent in ganglia reactivates to produce zoster (shingles). Neurological complications of zoster are increased in the aging population whose cell-mediated immunity to VZV is reduced. During varicella, virus enters ganglia by hematogenous spread or by retrograde axonal transport from skin infected by tonsillar memory CD4+ T cells. VZV-specific T cells are not essential to maintain latency in ganglia. Virus latency and reactivation is probably regulated by an innate immune response involving cytokines or chemokines. We developed an experimental animal model that parallels VZV infections in humans. Natural infection of primates with simian varicella virus (SW) leads to ganglionic latency and reactivation after irradiation and treatment with immunosuppressive drugs. Reactivation of SW is accompanied by changes in cytokine levels and by appearance of T cell clusters adjacent to neurons in ganglia with reactivated virus. These data provide the rationale for our hypothesis that both immune cells and non-immune cells as well as cytokines released by these cells upon their interaction with neurons are important determinants of the course of primary varicella, latency and reactivation. To determine the route of SW infection of skin and sensory ganglia, we will identify the host cell types and their role in the transport and establishment of SW infection in skin and in ganglia after primary infection (Aim 1). Because, SW latency and reactivation in ganglia are more likely regulated by an innate immune response involving cytokines, we will comparethe cytokine expression during latency and reactivation in monkey ganglia (Aim 2). To identify the SW-specific T cell response in ganglia during reactivation, we will identify the phenotype and specificity of T cells infiltrating ganglia during SW reactivation (Aim 3). A comprehensive knowledge of the cell types and immunological factors that influence the transport of SW from the site of primary infection to skin and sensory ganglia along with an understanding of the local SVV-specific T cell response in ganglia during latency and reactivation will identify potential targets for prevention of zoster in humans. The latter is of particular importance in the rapidly increasing elderly and immunocompromised populations, who often develop chronic and sometimes fatal neurological disease produced by VZV reactivation.