The principal objective of these studies is to determine host and viral factors that influence the genetically-controlled resistance of inbred mouse strains to street rabies virus (SRV). Studies concerning the importance of interferon induced within the central nervous system (CNS) during infection as a mechanism responsible for resistance have been completed. The interferon was characterized as a typical viral-induced pH 2.0 stable type l interferon with alpha and beta specificity. Furthermore, it was determined that the high concentrations of interferon-alpha/beta that were induced by SRV in the CNS of susceptible A/WySnJ mice were ineffective in inhibiting viral relication. The 100% survival of SRV-infected resistant SJL/J mice following neutralization of interferon within their CNC with high concentrations of rabbit anti-mouse interferon-alpha/beta suggested that the minimal amount of interferon present in the CNS during infection was not the mechanism responsible for their innate resistance to ip-inoculated SRV. Studies concerning the significance of cellular immunity have progressed with the development of a 8 hr assay that measures specific cytotoxic T-cell killing. Maximum killing occurs following a 5 day in vitro incubation of 1X108 spleen cells with 1X106 137Cs-irradiated rabies virus-infected stimulator cells; effector to target (E:T) ratios of 10 and 5 result in >70% and >40% specific lysis, respectively. The assay has been simplified by using P815, EL-4 and mouse neuroblastoma target cells persistently- infected with ERA virus. We have demonstrated specific T-cell cytotxicity with lymphocytes from susceptible A/WySnJ and C57Bl/6J mice and resistant DBA/2J and BALB/cByJ mice. Preliminary results suggest that maximum cytotoxic T-cell activity occurs seven days after ip-infection with ERA virus grown in CER cells. Mice infected with similar concentrations of SRV, CVS, and ERA viruses inoculated ip. as 10% mouse brain suspensions have minimal T-cell activity. We have been unable to demonstrate specific T-cell killing in an 8 hr assay with uncultured lymphocytes. The emphasis of these studies will be to continue to investigate the importance of cytotoxic T cells in murine resistance to SRV infections.
