IMMUNOBIOLOGY OF VARICELLA AND ZOSTER IN A PRIMATE MODEL

水痘带状疱疹病毒(VZV)引起水痘，潜伏在神经节内，主要在老年人重新激活，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)、脊髓炎、脑膜脑炎、视网膜炎、血管病变和多发性眼病。由于VZV是一种独有的人类病毒，致病机理和免疫生物学的研究一直很困难。灵长类动物自然感染水痘病毒会导致神经节细胞潜伏，并在免疫抑制及社会和环境应激后重新激活。最近，我们发现在无皮疹的情况下，肺炎链球菌以血源性方式感染猴神经节，在原发感染过程中，肺内的肺泡巨噬细胞和/或树突状细胞以及血液中的记忆T细胞被感染。在神经节、淋巴结和邻近血管的皮肤病变中都发现了受短波感染的T细胞。因为肺、淋巴结和神经节在皮疹出现之前就被感染了，最显著的组织病理学变化发现在肺和淋巴结，这项建议主要集中在这些器官和血液，在初次感染和再激活期间。带状疱疹后早期，神经节中COB T细胞的存在与CXCL10的表达有关，而与sw抗原的表达无关，而sw DNA和丰富的抗原存在于淋巴结中。这些集体发现为我们的假设提供了理论基础：(1)在初次感染期间，呼吸道常驻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，从而将病毒传播到多个器官；(2)在重新激活期间，除了通过轴突将病毒转移到皮肤外，SW还感染了神经节中受趋化因子吸引的T细胞和可能的其他免疫细胞，后者将Sw转移到淋巴和肺部。在初次感染和早期再激活期间，我们将鉴定受SW感染的细胞类型，并分析血液、肺和淋巴结中的抗SW免疫反应(目标1)，并分析在早期初次感染和早期再激活期间，神经节中的抗SW免疫反应(目标2)。全面了解在初次感染和复活期间传播带状疱疹病毒所涉及的细胞类型将有助于确定预防带状疱疹的潜在目标。后者在快速增长的老年人和免疫功能受损的人群中尤其重要，他们会患上VZV重新激活导致的慢性、有时是致命的神经系统疾病。

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.