The DA strain of Theiler's murine encephalomyelitis virus persists in the white matter of the spinal cords of susceptible mice. Previous results showed that the difference in susceptibility to viral persistence between the susceptible SJL/J strain and the resistant B10.S strain was due to multiple non-H-2 loci. The respective roles of hematopoietic and nonhematopoietic cells in this difference have been evaluated with bone marrow chimeras. The results show that non-H-2 loci with a major effect on susceptibility are expressed in hematopoietic cells. However, the study of the SJL.B10-D10Mit180-D10Mit74 congenic line suggests that other loci expressed in nonhematopoietic cells also play a role.The primary demyelinating disease induced by Theiler's murine encephalomyelitis virus is studied as an animal model for multiple sclerosis (13,16). After intracranial inoculation, the DA strain of Theiler's virus replicates in neurons of the brain and spinal cord in all strains of mice (30). This encephalomyelitis disappears after 2 weeks regardless of the mouse genotype. However, in genetically susceptible mice the virus persists for the lifetime of the animal in the white matter of the spinal cord in oligodendrocytes, macrophages, and possibly astrocytes (3,15,18,25,26) and induces chronic inflammation and primary demyelination (1,8,17,22). A previous study accounted for the variation of viral RNA level in 17 inbred strains by the interaction of two groups of loci (11). One locus with a major effect was named Tmevp1 for Theiler's murine encephalomyelitis virus persistence locus 1. It is located on chromosome 17 in the H-2D region. Several reports strongly suggest that the same locus controls not only viral persistence but also demyelination (14,20,27,29) and that the H-2D b class I gene plays a major role in resistance to both (4,19,28). The existence of non-H-2 susceptibility loci is shown by the fact that the SJL/J strain is more susceptible to viral persistence than the B10.S strain, although both bear the same H-2 s haplotype (11). Two of these non-H-2 loci, named Tmevp2 and Tmevp3, have been located on chromosome 10 close to Ifng by studying an F 1 (SJL/J ϫ B10.S) ϫ B10.S backcross and SJL/J lines congenic for different B10.S genetic intervals of chromosome 10 (7, 10). However, the Ifng gene does not explain the effect of either Tmevp2 or Tmevp3 (7, 24). One of these studies also showed that other susceptibility loci, with minor effects, must contribute to the difference in viral RNA load between these two mouse strains (10).The non-H-2 loci responsible for the difference in susceptibility between the SJL/J and the B10.S strains could affect the efficiency of the immune response against the virus or the viral life cycle. To distinguish between these possibilities, we measured the viral RNA load in bone marrow chimeras between these two immunocompatible H-2 s strains. The SJL.B10-D10Mit180-D10Mit74 congenic line, which has a small B10.S genetic interval containing the Tmevp3 locus (7), was also studied in an attempt to ...
We show that inactivating the  2 m gene increases the viral load of SJL/J mice persistently infected by Theiler's virus. Together with previous results, this shows that the characteristics of Tmevp1, a locus which controls the amount of viral RNA that persists in the central nervous system, are those of an H-2 class I gene.The DA strain of Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, is responsible for a biphasic neurological disease of mice. The first phase is an acute encephalomyelitis which takes place during the first 2 weeks that follow intracerebral inoculation. During the second phase, which occurs only in susceptible animals and is lifelong, persistent infection of the white matter of the spinal cord causes chronic inflammation and primary demyelination (14,15). This natural disease is considered one of the best models for multiple sclerosis (13,20).The extent of demyelination and the amount of viral RNA that persists in the central nervous system (CNS) vary greatly among inbred mouse strains (8). A locus with a major effect on both phenotypes has been mapped by several groups to the H-2D region of the major histocompatibility complex (MHC) (10,12,17,21,23). This locus has been named Tmevp1 for Theiler's murine encephalomyelitis virus persistence locus 1. Three phenotypes have been defined for the amount of viral RNA that persists in the CNS. Resistant strains clear the infection, and their F 1 crosses with the SJL/J strain clear the infection as well. Strains of intermediate susceptibility clear the infection, but their F 1 crosses with the SJL/J strain do not and are infected at high levels. Finally, susceptible strains remain persistently infected at high levels. In 15 of 16 mouse strains examined in one study, the viral RNA load was determined by the Tmevp1 haplotype. The H-2 b haplotype was associated with resistance, the H-2 q haplotype was associated with susceptibility, and the H-2 d , H-2 k , and H-2 s haplotypes were associated with intermediate levels of susceptibility (10). The SJL/J strain was the only strain which was more susceptible than predicted by its H-2 s haplotype. In subsequent work, its susceptibility was explained by non-H-2 loci, which have been mapped, on the mouse genome (9). Two of these loci are located close to each other on the telomeric part of chromosome 10 (6). Interestingly, multiple susceptibility loci located in the same region have also been reported for other phenotypes induced by Theiler's virus infection and for other diseases. ) were inoculated intracerebrally with 10 4 PFU of the DA1 strain of TMEV and studied during the acute (6 days postinoculation [p.i.]) and the chronic phase (21 and 45 days p.i.) of the infection. DA1 is a molecularly cloned TMEV DA strain produced from the infectious pTMDA1 plasmid (18,19). The amount of viral RNA in the CNS was measured by using a dot blot assay (1, 10). Briefly, for each mouse, fivefold dilutions of total RNA were dotted onto a filter and hybridized with either a viral cDNA probe or a control -acti...
Theiler’s virus causes a persistent infection and a demyelinating disease of mice which is a model for multiple sclerosis. Susceptibility to viral persistence maps to several loci, including the interferon gamma locus. Inactivating the gene coding for the interferon gamma receptor makes 129/Sv mice susceptible to persistent infection and clinical disease, whereas inactivating the interferon gamma gene makes C57BL/6 mice susceptible to persistent infection but not to clinical disease. This difference in phenotype is due to the difference in genetic background. Clinical disease depends on high viral load andTmevd5, a locus on chromosome 11. These results have consequences for the identification of viruses which might be implicated in multiple sclerosis.
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