The effect of interferon treatment in rabies prophylaxis in immunocompetent, immunosuppressed, and immunodeficient mice.

Abstract

The development of rabies is modulated by many interacting factors, most of which are dependent on the host immune response. For this reason, we studied the action of interferon (IFN) treatment on street rabies virus infection in mice, immunocompetent or immunosuppressed with cyclophosphamide. In immunocompetent mice, paralysis of hind limbs is the first symptom characteristic of rabies disease before weight loss and general prostration leading to death. Paralysis does not occur in immunosuppressed mice, which develop a shaggy hair and eventually lose weight and die. Administration of interferon (10(5) units, intraperitoneally) 1 h after virus inoculation and every 24 h led to a delay in the onset of first disease signs, but in general did not rescue immunocompetent or immunosuppressed mice from death. In both types of mice, rabies virus production in the brain was reduced by 1 log in response to IFN treatment. In immunocompetent mice treated with IFN, there was a significant increase of antibody synthesis against rabies virus. As expected, antibody synthesis in immunosuppressed mice was almost negligible. However, in mice treated with IFN and cyclophosphamide there was still significant antibody synthesis specific for rabies virus. IFN administered intravenously, subcutaneously, or intraperitoneally crosses the blood-brain barrier to cause enhanced levels of the two double-stranded RNA-dependent enzymes, the protein kinase and 2',5'-oligoadenylate (2-5A) synthetase in the brain. However in spite of this effect, IFN treatment seems to be unable to prevent the evolution of rabies disease in immunocompetent and immunosuppressed mice. Since the suppressing effect of cyclophosphamide is nonselective on both the cellular and humoral immune responses of mice, we investigated the action of IFN in rabies virus-infected athymic nude mice, which lack T cells. Athymic nude mice infected with street rabies virus become cachectic and die without any apparent symptom of paralysis of hind limbs. IFN treatment (administered as above) protected nude mice against rabies infection. Three months after virus inoculation and 2 months after the end of IFN treatment, 7 of 8 IFN-treated mice remained in perfect health. These results illustrate that the efficacy of IFN treatment against the evolution of rabies disease in mice is dependent on the suppression of the T-cell-mediated immune response of the host.