Distribution of Rabies Virus, Interferon an dInterferon-mediated Enzymes in the Brains of Virus-infected Rats

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SUMMARY The distribution of rabies virus, interferon and interferon-mediated enzymes, pppA(2'p5'A)n synthetase (2-5A synthetase) and poly(rI).poly(rC)-Sepharose-bound protein kinase, was studied in different regions of the brains of rabies virus-infected rats. A broad range of virus infectivity was found in the brain stem, cerebellum, cortex, hippocampus and striatum. Similarly, the levels of interferon were variable (2500 to 60000 units/mg protein in tissue extracts) in the different brain regions studied but were unrelated to the corresponding infectivities. The level of 2-5A synthetase and protein kinase was enhanced several-fold in the individual brain regions and the degree of such enhancement was correlated with the level of interferon. The production of interferon has been detected in the brain of animals during infection by various different viruses (Vil~ek, 1964; Finter, 1965; Luby et al., 1971 ; Tongaonkar & Ghosh, 1973). Like these viruses, rabies virus infection of mice results in the induction of interferon in the brain (Stewart & Sulkin, 1966; Wiktor et al., 1972; Marcovistz et al., 1984). This production of interferon is probably responsible for the high levels of interferon circulating in the blood. Interferon in brain extracts and in the plasma of rabies virus-infected mice is of type I: it is stable at pH 2 and is neutralized by antibodies against mouse ct +/~ interferons. In addition to the production of interferon, we have recently shown that the levels of two interferon-mediated enzymes, pppA(2'p5'A)n synthetase (2-5A synthetase) and protein kinase, are enhanced significantly in different organs as well as in the brain of mice infected with rabies virus (Marcovistz et al., 1984). Since similar results (unpublished) have been obtained in rats infected with rabies virus, we now report the regional distribution of virus, interferon, 2-5A synthetase and protein kinase in the brains of virus-infected rats. The CVS fixed strain of rabies virus, passaged in mouse brain, was used in these experiments. White Wistar rats (70 to 90 g) were inoculated into the footpad and after the onset of paralysis, the rats were killed and the brains were dissected (KSnig & Klippel, 1967; Tsiang, 1982). The infectivity of rabies virus in tissue extracts of the different brain regions was titrated in mice as described in World Health Organization Monograph number 23 (1973). Rat interferon activity was measured by inhibition of the cytopathic effect of vesicular stomatitis virus (VSV) on NRK- 49F cells (Wood & Hovanessian, 1979). The activity of interferon in the different regions of the brain was estimated by the level of 2-5A synthetase and protein kinase: both enzymes were assayed after partial purification on poly(rl).poly(rC)-Sepharose (Hovanessian et al., 1977, 1983). Table 1 gives the infectivity of rabies virus per mg protein for different regions of the brain assayed in parallel with the level of interferon per mg protein. These were found to be unrelated. The highest level of interferon was detected in the brain stem (60000 units/mg protein) whereas the lowest was found in the striatum (2500 units/mg protein). For the distribution of virus, the brain stem, the cortex and the striatum showed much higher viral infectivity than the cerebellum and the hippocampus. There was little correlation in each of these regions between the level of interferon and the virus infectivity. For example, there were comparable virus titres in the brain stem and cortex but the level of interferon in the cortex was one-third of that in the brain stem.

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