Reconstitution with T lymphocytes protects nude mice from a central nervous system disorder induced by a temperature-sensitive vesicular stomatitis virus.

Abstract

A temperature-sensitive mutant of vesicular stomatitis virus (VSV), tsG31-KS5 VSV, intracerebrally inoculated into BALB/c (+/+) or Swiss outbred mice yielded a clinically asymptomatic persistent infection of the central nervous system (CNS). BALB/c nude (nu/nu) mice infected with tsG31-KS5 VSV, however, all perished within 26 days of infection. All the nude mice were afflicted with a slowly progressing CNS disorder, with symptoms including lethargy, curvature of the spine, hind-limb paralysis and other neurological disorders, before they succumbed to the infection. Wild-type (wt) VSV infection of either normal or nude mice, on the other hand, invoked a rapidly lethal disease with all animals dying within 4 days of infection. When nude mice were reconstituted with 5 x 10(6) syngeneic T lymphocyte-enriched splenocytes, over 70% of them not only survived the tsG31-KS5 VSV infection but appeared to be free of any neurological disorders. Only 20% of these reconstituted mice infected for 20 days with tsG31-KS5 VSV endured a wt VSV challenge. In contrast, BALB/c (+/+) mice infected for 20 days with tsG31-KS5 VSV all survived a wt VSV challenge. Reconstitution of nude mice with 5 x 10(6) T lymphocytes did not elicit a vigorous secondary humoral antibody response against VSV. All the animals reconstituted with 5 x 10(7) T lymphocytes and infected with tsG31-KS5 VSV, however, had both late and early humoral responses that equalled antibody responses of BALB/c (+/+) mice. Reconstitution with either 5 x 10(6) or 5 x 10(7) T lymphocytes afforded the nude mice equivalent protection from the CNS disorder triggered by tsG31-KS5 VSV. Reconstitution with 5 x 10(6) T lymphocytes, therefore, protected nude mice from the neurological disease induced by the persistent virus without eliciting a robust humoral antibody response. Infectious, temperature-sensitive VSV was retrieved from the CNS of the nude mice that had been reconstituted with 5 x 10(6) T lymphocytes and infected for up to 30 days with tsG31-KS5 VSV. The CNS-isolated VSV was less temperature-sensitive than tsG31-KS5 VSV. When the CNS-isolated VSV was intracerebrally inoculated into Swiss outbred mice, an aggressive disease ensued with most of the mice developing a CNS disorder. In comparison, Swiss outbred mice were asymptomatically infected with tsG31-KS5 VSV. The VSV isolated from the CNS was more lethal to the mice than tsG31-KS5 VSV possibly because it was less temperature-sensitive.