Abstract
Herpes simplex encephalitis (HSE) is characterized by severe focal brain inflammation leading to substantial loss of nervous tissue. The authors established a model of Herpes simplex virus type 1 (HSV)-1–induced acute encephalitis in the rat by injecting into the whiskers' area a virus strain isolated from a fatal human HSE case. The model might resemble natural propagation of HSV-1 in humans; spreading from the mouth and lips via the trigeminal nerve to trigeminal ganglia and subsequently entering the central nervous system (CNS). HSV-1 infected Dark Agouti (DA) rats developed a well-synchronized disease and died 5 days after inoculation. HSV-1 detection by quantitative polymerase chain reaction (qPCR), virus isolation and immunohistochemistry, magnetic resonance imaging, and histopathological examination verified dramatic encephalitis mainly in the brainstem, but also in the olfactory bulb and other segments of the brain of diseased rats. In contrast, Piebald Virol Glaxo (PVG) rats were completely resistant to disease, displaying a more rapid clearance of peripheral infection and no evidence of virus entering into neither the trigeminal ganglia nor the CNS. These results suggest a regulation of susceptibility to HSV-1–induced encephalitis at the level of peripheral infection and subsequent neuronal uptake/transport of the virus. This provides a basis for future positioning of genetic polymorphisms regulating HSE and for dissection of important pathogenetic mechanisms of this severe human disease.
This work was supported by 6th Framework Program of the European Union, NeuroproMiSe, LSHM-CT-2005-018637, and the EURATools, LSHG-CT-2005-019015, as well as by grants from the Wadsworth Foundation, Torsten and Ragnar Söderbergs Foundation, The Foundation for the Memory of Sigurd and Elsa Golje, Hjärnfonden, The Swedish Society for Medical Research, Björklunds Foundation, Nils and Bibbi Jenssens Foundation, Montel Williams Foundation, Magnus Bergvalls Foundation, Swedish Science Council, and The Swedish Association of Persons with Neurologically Disabilities. The authors would like to thank Maria Johansson for skilled work with the virological analyses and the employees at the Astrid Fagræus laboratory of the Swedish Institute for Infectious Disease Control for taking excellent care of the rats. The experimental MRI unit is a core facility supported by Karolinska University Hospital and Karolinska Institutet.