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: 8636736
• 负责人: RAVI MAHALINGAM
• 金额: $ 86.73万
• 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/8636736
• 关键词: Age; Alveolar Macrophages; American; Antigens; Autopsy; Blood; Blood Vessels; CD8B1 gene; CXCL10 gene; Cell Communication; Cells; Cellular Immunity; Chickenpox; Chronic; Clinical; Collaborations; DNA; Dendritic Cells; Disease; Elderly; Exanthema; Flow Cytometry; Ganglia; Herpes zoster disease; Herpesvirus Type 3; Human; Human Virus; Immune; Immune response; Immunization; Immunobiology; Immunocompromised Host; Immunosuppression; In Situ; Infection; Infiltration; Intervention; Knowledge; Lung; Lymphocyte; Meningoencephalitis; Modeling; Molecular; Monkeys; Myelitis; Netherlands; Neurologic; Neurons; Organ; Pathogenesis; Patients; Persons; Population; Postherpetic neuralgia; Prevention; Primates; Retinitis; Skin; Stress; T memory cell; T-Lymphocyte; Testing; Time; Tissues; Transcript; Translating; Vaccinated; Vascular Diseases; Viral Antigens; Virus; Virus Diseases; Work; base; cell type; chemokine; experience; lymph nodes; nervous system disorder; neurotropic; novel; prevent; reactivation from latency; skin lesion; social; virus host interaction

Varicella zoster virus (VZV) causes varicella, becomes latent in ganglia, and reactivates mostly in the elderly to cause zoster and other serious neurological complications including postherpetic neuralgia (PHN), myelitis, meningoencephalitis, retinitis, vasculopathy and multiple ocular disorders. Because VZV is an exclusively human virus, studies of pathogenesis and immunobiology have been difficult. Natural infection of primates with simian varicella virus (SW) leads to ganglionic latency and to reactivation during immunosuppression and after social and environmental stress. Recently, we showed that SW infects monkey ganglia hematogenously in the absence of rash, and that during primary infection, alveolar macrophages and/or dendritic cells in lungs and memory T cells in blood become infected. SW-infected T cells are found in ganglia, lymph nodes and in skin lesions adjacent to blood vessels. Because lung, lymph node and ganglia are infected before skin rash appears, with the most pronounced histopathological changes found in lungs and lymph nodes, this proposal focuses primarily on these organs and blood, both during primary infection and reactivation. At early times after zoster, the presence of COB T cells in ganglia correlates with expression of CXCL10 but not with SW antigen, while SW DNA and abundant antigen are seen in lymph nodes. These collective findings provide the rationale for our hypothesis that: (1) during primary infection, airway-resident lymphocytes become infected and transfer virus to memory T-cells in draining lymph nodes, which disseminate virus to multiple organs; and (2) during reactivation, in addition to transaxonal transport of virus to-skin, SW infects chemokine-attracted T cells and possibly other immune cells in ganglia which transport SW to lymph nodes and lungs. We will identify, during primary infection and early reactivation, SW-infected cell types and analyze the anti-SW immune response in blood, lungs and lymph nodes (Aim 1) and analyze, during early primary infection and early reactivation, the anti-SW immune response in ganglia (Aim 2). A comprehensive knowledge of the cell types involved in dissemination of SW during primary infection and reactivation will help identify potential targets for prevention of zoster. The latter is of particular importance in the rapidly increasing elderly and immunocompromised populations, who develop chronic and sometimes fatal neurological disease produced by VZV reactivation.

水痘带状疱疹病毒（VZV）引起水痘，在神经节中潜伏，并且主要在老年人中重新激活以引起带状疱疹和其他严重的神经系统并发症，包括带状疱疹后神经痛（PHN）、肌萎缩、脑膜脑炎、视网膜炎、血管病变和多种眼部疾病。由于VZV是一种专属于人类的病毒，其发病机制和免疫生物学的研究一直很困难。灵长类动物自然感染猴水痘病毒（SW）导致神经节潜伏期，并在免疫抑制和社会和环境压力后重新激活。最近，我们发现SW在没有皮疹的情况下通过血液感染猴神经节，并且在初次感染期间，肺泡巨噬细胞和/或肺中的树突状细胞和血液中的记忆T细胞被感染。SW感染的T细胞存在于神经节、淋巴结和血管附近的皮肤病变中。由于肺、淋巴结和神经节在皮疹出现之前就已被感染，肺和淋巴结的组织病理学变化最明显，因此该建议主要关注这些器官和血液，包括原发感染和再激活期间。在带状疱疹后早期，神经节中COB T细胞的存在与CXCL 10的表达相关，但与SW抗原无关，而在淋巴结中观察到SW DNA和丰富的抗原。这些共同的发现为我们的假设提供了理论基础：（1）在原发性感染期间，气道驻留淋巴细胞被感染并将病毒转移到引流淋巴结中的记忆T细胞，记忆T细胞将病毒传播到多个器官;和（2）在再活化过程中，除了病毒向皮肤的经轴突转运外，SW感染趋化因子吸引的T细胞和神经节中可能的其他免疫细胞，这些细胞将SW运输到淋巴结和肺。我们将在初次感染和早期再激活期间识别SW感染的细胞类型，并分析血液、肺和淋巴结中的抗SW免疫应答（目的1），并在早期初次感染和早期再激活期间分析神经节中的抗SW免疫应答（目的2）。全面了解原发性感染和再激活期间参与SW传播的细胞类型将有助于确定预防带状疱疹的潜在目标。后者在迅速增加的老年人和免疫功能低下的人群中特别重要，这些人群会因VZV再激活而患上慢性甚至致命的神经系统疾病。