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.
Characterization of cell types involved in dissemination of VZV to multiple organs during primary infection and reactivation in the primate SW model will translate to intervention strategies, not only to limit establishment of latency, but also to prevent virus reactivation which results in serious neurological and ocular disease, primarily in elderly humans.
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