Analysis of the molecular basis of neuropathogenesis of RNA viruses in experimental animals: relevance for human disease?

Abstract

RNA viruses with segmented genomes were the first model used for molecular analysis of viral neuropathogenesis, since they could be analysed genetically by reassortment. Four viruses with non-segmented genomes have been used as models of neurovirulence and demyelinating disease: JHM coronavirus, Theiler's virus, Sindbis virus and Semliki Forest virus (SFV). Virus gene expression in the central nervous system of infected animals has been measured by in situ hybridization and immunocytochemistry. Cell tropism has been analysed by neural cell culture. Infectious clones have been constructed for Theiler's virus, Sindbis virus and SFV, and these allow analysis of the sequences involved in the determination of neuropathogenesis, through the construction of chimeric viruses and site-specific mutagenesis. Measles and rubella viruses have been studied in animal systems because of their importance for human disease. The importance of two recently discovered mechanisms of neuropathogenesis, antibody-induced modulation of virus multiplication, and persistence of virus in the absence of multiplication, remains to be assessed.

Transient virus infection and multiple sclerosis

“…Laboratory virus infections of mice and rats have also been used as models to understand the processes of virus-induced demyelination. These experimental models include murine coronavirus, where persistent virus infection induces an EAE-like disease [22,34]. Myelin reactive T cells are also observed following experimental infection of rats with measles virus and some of these T cell lines are encephalitogenic, supporting the hypothesis that a virus trigger can lead to autoimmunity and myelin damage [35±37].…”

“…Another virus model of MS is Theiler's murine encephalomyelitis virus (TMEV) infection of mice, which produces a chronic demyelinating disease associated with virus persistence [10,11,22,23,38].…”

Are virus infections triggers for autoimmune disease?

“…On the other hand, exacerbations of MS have been correlated with viral infections (30)(31)(32)(33). Several animal models of MS are based on viral infections; for example, canine distemper virus infection of dogs, visna virus infection of sheep, and murine coronavirus and Theiler's murine encephalomyelitis virus infection of mice (11,29,(34)(35)(36)(37). The presence of persistent virus infection in these animals results in demyelination with characteristic features similar to MS in humans.…”

The 5′ untranslated region as a pathogenicity determinant of Semliki Forest virus in mice

“…Semliki Forest virus (SFV) is a positive-stranded RNA alphavirus of the Togaviridae family which has been extensively studied as a model of viral neuropathogenesis [1]. The existence of several strains of SFV which differ in neuropathogenicity in mice has allowed comparative analysis between them at the molecular level through the availability of SFV infectious cDNA clones [2][3][4][5].…”