Long noncoding RNAs (lncRNAs) are increasingly appreciated as regulators of cell-specific gene expression. Here, an enhancer-like lncRNA termed NeST (Nettoie Salmonella pas Theiler’s; cleanup Salmonella not Theiler’s) is shown to be causal for all phenotypes conferred by murine viral susceptibility locus Tmevp3. This locus was defined by crosses between SJL/J and B10.S mice and contains several candidate genes, including NeST. The SJL/J-derived locus confers higher lncRNA expression, increased interferon-γ abundance in activated CD8+ T cells, increased Theiler’s virus persistence and decreased Salmonella enterica pathogenesis. Transgenic expression of NeST lncRNA alone was sufficient to confer all phenotypes of the SJL/J locus. NeST RNA was found to bind WDR5, a component of the histone H3 lysine 4 methytransferase complex, and to alter histone 3 methylation at the interferon gamma locus. Thus, this lncRNA regulates epigenetic marking of IFNγ-encoding chromatin, expression of IFN-γ and susceptibility to a viral and a bacterial pathogen.

The Tmevp3 locus controls the load of Theiler's virus RNA during persistent infection of the mouse central nervous system (CNS). We identified a candidate gene at this locus, Tmevpg1, by using a positional cloning approach. Tmevpg1 and its human ortholog, TMEVPG1, are expressed in the immune system and encode what appears to be a noncoding RNA. They are located in a cluster of cytokine genes that includes the genes for gamma interferon and one or two homolog of interleukin-10. We now report that Tmevpg1 is expressed in CNS-infiltrating immune cells of resistant B10.S mice, but not in those of susceptible SJL/J mice, following inoculation with Theiler's virus. The pattern of expression of Tmevpg1 is the same in B10.S mice and in SJL/J mice congenic for the resistant B10.S haplotype of Tmevp3. Nineteen polymorphisms were identified when the Tmevpg1 genes of B10.S and SJL/J mice were compared. Interestingly, Tmevpg1 is down regulated after in vitro stimulation of murine CD4 ؉ or CD8 ؉ splenocytes, whereas Ifng is up regulated. Similar patterns of expression of TMEVPG1 and IFNG were observed in human NK cells and CD4 ؉ and CD8 ؉ T lymphocytes. Therefore, Tmevpg1 is a strong candidate gene for the Tmevp3 locus and may be involved in the control of Ifng gene expression.After intracranial inoculation, the DA strain of Theiler's virus replicates for approximately 2 weeks in neurons of the mouse brain and spinal cord, regardless of the mouse's genetic background. Some genetically resistant mice clear the infection at this stage. Others, which are susceptible to persistence of the infection, remain infected for life (26). However, in this case, the virus does not persist in neurons. Instead, it is found in glial cells of the white matter of the spinal cord. Persistent infection of the white matter induces chronic inflammation and primary demyelination similar to those seen in multiple sclerosis (25). Susceptibility to viral persistence varies greatly among inbred strains of mice. The viral genome load during persistent infection is controlled mainly by the H2D class I gene (4-6, 24). However, the SJL/J strain is the only inbred strain among 16 examined for which the viral genome load is greater than that predicted by its H2 s haplotype (13). Studies of bone marrow chimeras of the SJL/J and B10.S strains, which both bear an H2 s haplotype, showed that susceptibility loci with major effects on persistence are expressed in cells of the immune system (3). Some non-H2 susceptibility loci were mapped by using a backcross and congenic mice between the SJL/J and B10.S strains. Two susceptibility loci, Tmevp2 and Tmevp3, were located on chromosome 10 close to the Ifng locus (8, 12). However, immunological studies indicated that the Ifng gene does not explain the effects of the Tmevp2 or the Tmevp3 locus (30). Instead, the Tmevpg1 gene was recently identified by positional cloning of the Tmevp3 locus. It is located telomeric to a cluster of cytokines, which includes the Ifng and IL-22/Il-Tif genes (36). Tmevpg1 has six exons and ap...

Theiler's virus causes a persistent and demyelinating infection of the central nervous system of the mouse, which is one of the best animal models to study multiple sclerosis. This review focuses on the mechanism of persistence. The virus infects neurons for a few weeks and then shifts to white matter, where it persists in glial cells and macrophages. Oligodendrocytes are crucial host cells, as shown by the resistance to persistent infection of mice bearing myelin mutations. Two viral proteins, L and L*, contribute to persistence by interfering with host defenses. L, a small zinc-finger protein, restricts the production of interferon. L*, a unique example of a picornaviral protein translated from an overlapping open reading frame, facilitates the infection of macrophages. Susceptibility to persistent infection, which varies among inbred mouse strains, is multigenic. H2 class I genes have a major effect on susceptibility. Among several non-H2 susceptibility loci, Tmevp3 appears to regulate the expression of important cytokines.

SummaryThe Daniels strain of Theiler's virus causes a persistent infection of the white matter of spinal cord of susceptible mice, with chronic inflammation and primary demyelination. Inbred 129Sv mice are resistant to this infection; they present with mild encephalomyelitis and clear the infection within a matter of days. A very different outcome was observed with inbred 129Sv mice whose receptors for interferon ot//~ or interferon 3' had been inactivated by homologous recombination. The former presented severe encephalomyelitis with acute infection of neurons, particularly in brain and hippocampus, and extensive infection with necrosis of the choroid plexus. Most animals died of this acute disease. The latter, presented the same early encephalomyelitis as the control 129Sv mice. However, they remained persistently infected and developed a very severe late infection of the white matter with extensive primary demyelination. This late disease looked like an exacerbated form of the chronic demyelinating disease observed in susceptible inbred mice such as the SJL/J or FVB strains. Our results show that the two interferon systems play nonredundant roles in the resistance of the 129Sv mouse to the infection by Theiler's virus. They also lend support to the notion that the Ifg gene is involved in the resistance/susceptibility of inbred strains of mice to persistent infection by this picornavirus.