Bone Marrow Chimeras Reveal Non-H-2Hematopoietic Control of Susceptibility to Theiler's Virus Persistent Infection

Abstract

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 ...

The Level of Viral Infection of Antigen-Presenting Cells Correlates with the Level of Development of Theiler's Murine Encephalomyelitis Virus-Induced Demyelinating Disease

“…It has previously been shown using bone marrow chimeras between resistant B10.S and susceptible SJL mice that hematopoietic cells exert a major effect on susceptibility to TMEV (25). We have also confirmed the role of hematopoietic cells in B6.S and SJL mice (data not shown).…”

Interleukin 22 Is a Candidate Gene forTmevp3, a Locus Controlling Theiler's Virus-Induced Neurological Diseases

“…In contrast we showed in another article that SJL.Tmevp3 B10S mice are more susceptible to persistent infection than the SJL parents when the mice are inoculated at 13-14 weeks of age (Aubagnac et al 2002). Study of bone marrow chimeras showed that this difference of viral load depends on the Tmevp3 allele of recipient strains with an SJL background.…”

“…Surprisingly, study of bone marrow chimeras between SJL.Tmevp3 B10S congenic mice and the parental strains revealed that 13-14-week-old SJL.Tmevp3 B10S mice are infected at a higher level than SJL mice (Aubagnac et al 2002), in contrast to the infection of 3-4-week-old mice in which the SJL.Tmevp3 B10S mice are infected at a lower level than the SJL mice. These opposite phenotypes for mice inoculated at different ages suggest that the effect of the Tmevp3 locus is due to the action of two genes: one responsible for the susceptibility of 3-4-week-old mice, when it bears the SJL allele, and the other responsible for the susceptibility of 13-14-week-old mice, when it bears the B10.S allele.…”

“…Reconstituted and 12-14-week-old control mice were anesthetized and inoculated intracerebrally as described above. The efficiency of the reconstitution was assessed with peripheral blood lymphocytes at the time of death for each mouse reconstituted with allogeneic bone marrow cells using PCR with D10Mit180 marker and/or FACScan and anti-Ly-9.1 antibodies as previously described (Aubagnac et al 2002). The degree of chimerism varied from 75 to 100%.…”

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

“…The best approach to confirm and narrow these localizations will be the production of congenic and polycongenic inbred strains, as it has been successful in other infectious, viral and immunological disease models. [40][41][42] An alternative approach, which may allow the identification of the causative gene(s) in each interval, is the characterization of relevant candidate genes. Multiple Figure 5 Genome-wide scan of 123 (A/J Â B10.A-H2 a )F2 individuals with extreme phenotypes.…”