Study of the mechanism of innate resistance to virus infection

Goodman, G. T.; Koprowski, H.

The resistance of mice to Arbor B viruses was investigated in crossbreeding and backcrossbreeding experiments between the virus-resistant PRI and BRVR mice, and the virus susceptible C3H/He mice. The results of challenging with virus mice from each of 8 backcross generations indicated that virus resistance is inherited as a single dominant gene. The susceptibility of mice from different backcross generations to spontaneous mammary adeno-carcinoma was unrelated to the presence of the gene for virus resistance. In the study of the physiological mechanisms of resistance, no virus was detected in the blood of resistant BRVR mice 16 hours after intraperitoneal inoculation with West Nile virus, while viremia persisted in susceptible C3H mice for 48 hours. Brain tissue of resistant mice supported, in contrast to susceptible mice, the multiplication of Arbor B viruses poorly in vivo and in vitro. The role of specific and non-specific virus inhibitors in the blood of mice was eliminated as a determining factor in virus resistance. Attempts were made to make PRI and BRVR mice more susceptible to Arbor B virus infection by depressing the function of their lymphoid tissue. Both total body irradiation and treatment with a sublethal dose of a radiomimetic drug, 6-thioguanine, increased the susceptibility of PRI and BRVR mice to the lethal effect of West Nile virus. Treatment of mice with bacterial endotoxin increased the susceptibility of both the susceptible and resistant strains of mice to parenteral infection with West Nile virus. Treatment with cortisone and blocking of the reticulo-endothelial system with Thorotrast were without effect. Newborn PRI mice, which were either runts or tolerant to C3H skin homografts as a result of neonatal treatment with C3H cells, died when inoculated with West Nile virus. fa contrast, neonatally treated PRI mice which rejected C3H skin homografts were resistant to virus infection. Susceptible C3H and BSVS mice became resistant to virus infection on rare occasions when treated with a lethal dose of 6-thioguanine, followed by an intravenous inoculation of lymphoid cells from resistant BRVR mice. Similar results were obtained when C3H mice were injected neonatally with resistant (BRVR x C3H) F1 lymphoid cells. Virus resistance was studied on a cellular level by comparing the level of multiplication of West Nile virus in infected tissue cultures prepared from resistant and susceptible mouse spleens, lungs, kidneys and peritoneal macrophages. Splenic macrophages from resistant and susceptible mice were found to release similar amounts of virus during the first 2 days in tissue culture. From the second day, however, macrophages of susceptible mouse origin supported virus multiplication while cultures from resistant mice released negligible amounts of virus. Cultures of cells from lungs and kidneys of resistant and susceptible mice produced equal amounts of virus. Spleen cell cultures from susceptible mouse tissue were more susceptible to a cytotoxic effect produced by high concentrations of either living or inactivated West Nile virus. When spleen cells were stained with fluorescein-labelled immune serum 2-6 days after exposure to virus, virus antigen was concentrated in a higher percentage of cells in susceptible mouse spleen cultures than in cells cultured from resistant mouse spleens. It appears from these findings that only a small fraction of the macrophage population of the susceptible mice was found to support the growth of West Nile virus. The difference between this population and that encountered in the resistant strain is sufficient for the functioning of the defense system, determining the innate resistance to virus infection.

Study of the mechanism of innate resistance to virus infection

Goodman, G.T.; Koprowski, H., 1962: Study of the mechanism of innate resistance to virus infection. Journal of Cellular and Comparative Physiology 59: 333-373