IMMUNOBIOLOGY OF VARICELLA AND ZOSTER IN A PRIMATE MODEL

灵长类动物模型中水痘和带状疱疹的免疫生物学

• 批准号: 7578632
• 负责人: RAVI MAHALINGAM
• 金额: $ 79.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7578632
• 关键词: Animals; Antibodies; Antigen-Presenting Cells; Antigens; Appearance; Autologous; Axonal Transport; Blood; CCR6 gene; Cell Differentiation process; Cells; Cellular Immunity; Chickenpox; Chronic; Confocal Microscopy; Data; Dendritic Cells; Differentiation Antigens; Down-Regulation; Elderly; Experimental Animal Model; Flow Cytometry; Ganglia; Gene Expression; Hematogenous Spread; Herpes zoster disease; Herpesviridae; Herpesvirus Type 3; Homing; Human; Immune; Immune response; Immunity; Immunobiology; Immunocompromised Host; Immunohistochemistry; Immunologic Factors; Immunosuppressive Agents; Incidence; Infection; Infectious Skin Diseases; Knowledge; Life; Lymphocyte Subset; MHC Class I Genes; Macaca; Modeling; Molecular Models; Monkeys; Monoclonal Antibodies; Myxoid cyst; Neurologic; Neurons; Papio; Pathogenesis; Pharmaceutical Preparations; Phenotype; Population; Prevention; Primates; Proteins; Protocols documentation; Reverse Transcriptase Polymerase Chain Reaction; Role; Route; Sensory Ganglia; Site; Skin; T-Cell Immunologic Specificity; T-Lymphocyte; TNFSF11 gene; Testing; Time; Tonsil; Transcript; Up-Regulation; Vaccinia virus; Viremia; Virus; Virus Diseases; Virus Latency; aging population; base; cell type; chemokine; cytokine; enhanced green fluorescent protein; experience; infected B cell; interleukin-17C; interleukin-19; irradiation; memory CD4 T lymphocyte; molecular modeling; nervous system disorder; protein expression; reactivation from latency; receptor; response

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.

原发水痘带状疱疹病毒(VZV)感染会产生水痘(水痘)，之后病毒会变成 潜伏在神经节中重新激活以产生带状疱疹(带状疱疹)。带状疱疹的神经系统并发症有 在对VZV的细胞免疫功能降低的老龄化人口中增加。在水痘期间， 病毒通过血源性传播或通过逆行轴突运输从感染的皮肤进入神经节 扁桃体记忆CD4+T细胞。VZV特异性T细胞不是维持神经节潜伏期所必需的。 病毒的潜伏和重新激活可能是由一种涉及细胞因子或 趋化因子。我们开发了一种与人类感染VZV相似的实验动物模型。 灵长类动物自然感染猴水痘病毒可导致神经节潜伏期和再激活 照射后给予免疫抑制药物治疗。软件的重新激活伴随着 神经节细胞因子水平的变化及邻近神经元的T细胞团的出现 重新激活的病毒。这些数据为我们的假设提供了理由，即免疫细胞和 非免疫细胞以及这些细胞在与其相互作用时释放的细胞因子 神经元是决定水痘发病过程、潜伏期和复活的重要因素。 为了确定皮肤和感觉神经节感染霉菌的途径，我们将鉴定宿主细胞类型 以及它们在皮肤和神经节原发感染中的传播和建立中的作用 感染(目标1)。因为，神经节中的软件延迟和重新激活更有可能由 涉及细胞因子的先天免疫反应，我们将比较潜伏期细胞因子的表达 和猴神经节的重新激活(目标2)。在神经节中识别Sw特异性T细胞反应 在重新激活过程中，我们将鉴定T细胞渗入神经节的表型和特异性 在软件重新激活期间(目标3)。全面的细胞类型和免疫学知识 影响Sw从原发感染部位向皮肤和感觉神经节转运的因素 以及对神经节中局部SVV特异性T细胞在潜伏期和 重新激活将确定预防人类带状疱疹的潜在靶点。后者是特别的 对迅速增长的老年人和免疫功能低下的人口的重要性，他们经常 患上由VZV重新激活引起的慢性、有时是致命的神经系统疾病。