In vivo and in vitro models of demyelinating disease. XVII. The infectious process in athymic rats inoculated with JHM virus

Abstract

Wistar Lewis (WL), Long Evans (LE) and other rat strains develop complete resistance to CNS disease when inoculated intracerebrally with murine hepatitis JHM virus (JHMV) after the 10th day of age. Two types of studies were conducted to ascertain the involvement of the cellular immune system in development of resistance. Immunosuppression of WL rats with cyclosporin A (CsA) following onset of the age-related resistance demonstrated that this drug was partially able to abrogate resistance. In the other studies nude (rnu/rnu) rats, their heterozygous (rnu/+) litter mates and genetically related LE rats of various ages were challenged with JHMV. The rnu/+ and LE animals became completely resistant before the age of weaning, whereas some rnu/rnu rats, challenged as late as 70 days of age, showed disease symptoms--albeit after a long latent period. These observations indicated that the cellular immune system plays an important role in suppressing the disease process in the CNS. When the infection of nude rats was initiated on or after the 15th day of life, the histological lesions were generally small and present in both grey and white matter but were seldom seen in the spinal cord. Mononuclear infiltrates were evident throughout the CNS. In some nude rats there was massive mononuclear cell infiltration towards the meningies and into ventricular spaces. By contrast in mu/+, LE and WL rats with late-onset disease symptoms, demyelinating-type lesions were confined to the white matter and only minor infiltration of mononuclear cells was evident. JHMV RNA was detectable by dot-blotting analysis in the CNS of both paralysed and asymptomatic rnu/rnu and rnu/+ rats, but less RNA was usually detected in heterozygous animals. In-situ hybridization with cDNA probes for JHMV RNA showed that neurons in the hippocampus and cerebellum, as well as cells in the white matter, were frequently infected. The present data indicate that in the rat T cells have an important function in maintaining resistance to the JHMV related disease process. However, even without a functional T cell compartment nude rats challenged after 15 days of age did not develop an acute encephalitis, suggesting that an age-dependent, non-immunological mechanism is also involved in restricting the spread of infection. It is possible that resistance in euthymic rats sets in because: (1) at the time of weaning the CNS matures, so that the number of targets available for infection is reduced, (2) T cells prevent the late-onset disease by clearing persistent, low grade infections from the CNS.