Viral load and a locus on chromosome 11 affect the late clinical disease caused by Theiler's virus

Abstract

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 and Tmevd5, a locus on chromosome 11. These results have consequences for the identification of viruses which might be implicated in multiple sclerosis.

FIG. 1

Amount of viral RNA in the central nervous system at different times p.i. The amount of viral RNA was measured in the brain on day 6 p.i. and in the spinal cord on days 21 and 45 p.i. This amount is expressed as the highest RNA dilution which gave a hybridization signal (left ordinate) or the score of viral persistence (right ordinate). n, number of animals per group. ∗, P < 0.05. The error bars indicate the SEM.

FIG. 2

Longitudinal sections of spinal cord from a C57BL/6 Ifng^−/− mouse (A) and a wild-type C57BL/6 mouse (B) with Theiler’s virus 45 days p.i. The arrows indicate infected cells detected by immunocytochemistry. Magnification, ×200 (A) and ×320 (B).

FIG. 3

Amount of viral RNA 45 days p.i. in the spinal cord of the two F₂ crosses and their parental strains. The amount of viral RNA is expressed as the highest RNA dilution (+ SEM) which gave a hybridization signal (left ordinate) or the score of viral persistence (right ordinate). n, number of animals per group. ∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001.

FIG. 4

Amount of viral RNA at 45 days p.i. in the spinal cords of asymptomatic (left) and symptomatic (right) mice.

FIG. 5

Amount of viral RNA 45 days p.i. in the spinal cords of asymptomatic (left-hand graphs) and symptomatic (right-hand graphs) mice as a function of genotype at the D11Mit179 locus. For each group of animals, the absolute number and the percentage of mice with a score of viral persistence equal or superior to 3.5 are given. These animals are indicated by hatched and solid boxes, respectively. Six asymptomatic mice died before 45 days p.i. (five were C57BL/6 homozygous, and one was 129/Sv homozygous for the D11Mit179 marker).