Development and characterization of a murine model to study herpes simplex encephalitis: Role of the cellular immune response in protection and pathology

Herpes simplex encephalitis (HSE) in man is characterized by focal lesions of hemorrhage and necrosis localized primarily to the inferior temporal lobe of the brain. Immunosuppressed patients with HSE lack the typical inflammatory changes, hemorrhagic necrosis, and localization of pathology to the inferior temporal lobe. This has led to the suggestion that the immune system may play a role in the pathogenesis of HSE. To evaluate the hypothesis that HSE is an immunopathogenic disorder mediated by virus-specific T cells we have developed a new murine model of this disease which more faithfully mimics HSE in humans. Intranasal infection of SJL mice with a clinical isolate of HSV-1 (strain H129) results in a pattern of encephalitis that is highly reminiscent of the disease that has been described in normal immunocompetent human beings. We have designated this pattern of encephalitis focal entorhinal necrotizing encephalitis (FERNE) to distinguish it from histologically different forms of encephalitis that occur in other strains of mice (e.g. C57BL/6), which lack pathological changes in the temporal area.Brain infiltrating mononuclear (BIM) cells from FERNE lesions in SJL mice were isolated and characterized. Phenotypic analysis revealed that the majority of cells recovered were CD3+ T cells (up to 70% of total cells), with CD4+ and CD8+ T cell subsets present in approximately a 1:1 ratio. Activated cells, detected by IL-2 receptor expression, comprised 30% of the total cells isolated. BIM cells from various brain regions of infected SJL and C57BL/6 mice were isolated and assayed for cytolytic activity using HSV-1 infected targets, and NK sensitive Yac-1 cells. Cells derived from the temporal area of infected SJL mice were directly cytotoxic for HSV-1 infected targets, while those from the temporal area of infected C57BL/6 mice were not. NK cell activity was not detected in SJL mice. Cells harvested from spleen, draining lymph nodes, or uninvolved areas of the brain from either mouse strain did not exhibit direct cytolytic activity. These studies revealed that cytotoxic T lymphocytes were associated with the presence of FERNE lesions in SJL mice