Nature of Inherited Resistance to Viruses Affecting the Nervous System

Abstract

Albino mice bred at the Princeton Rockefeller Institute (PRI) are 100% resistant in the adult stage to the 17D strain of yellow fever virus, whereas Swiss mice are 100% susceptible. Multiplication of the virus in the PRI mice occurred at a level only 1/10,000 to 1/100,000 of that achieved in Swiss mice. Genetic tests indicated that resistance to the virus was inherited as a single autosomal dominant factor. Newborn, 1- or 2-day-old PRI mice when inoculated with 17D virus, died after an incubation period of 10 days or longer; 3- to 5-day old mice behaved irregularly, and mice over 5 days behaved like the adults. Viral multiplication was as low in the suckling mice which died as in the adults, suggesting that the tissues of newborn mice were more vulnerable. Tests with intracerebral inoculations of the "French neurotropic" strain of yellow fever gave an avg. death rate of 24% among adult PRI mice, although viral multiplication was equally low in the mice which died and in those which stayed well, and the virus particles seemed to be the same in all cases. When crosses were made between PRI mice and Swiss mice the avg. mortality of the F1 animals was 84% after intracerebral inoculation. Back-crosses of F1 mice to PRI mice resulted in 60% mortality among the progeny. Crosses between resistant PRI mice and Swiss mice gave 46% mortality in the progeny. Crosses involving resistant PRI parents gave 18% mortality, compared to 31% mortality for crosses between susceptible PRI and resistant PRI mice. These results suggested that cell vulnerability was due to a recessive gene or genes, that the Swiss mice were probably homozygous recessive and that many of the unselected PRI stocks were heterozygous. There was also an indication that cellular vulnerability had a graded effect, producing weakness or paralysis, but not death, in a small proportion of mice. The genetic factor in PRI mice, which produced a low level of multiplication of yellow fever virus, had a similar effect on viruses of dengue fever, West Nile fever, Japenese B, St. Louis and Russian spring-summer encephalitis, all of which are linked by common antigens. No effect was produced on a number of other viruses tested. With the dengue viruses all PRI mice were uniformly resistant but with the West Nile, Japnese B and St. Louis viruses results varied depending on the strain used and the number of passages in Swiss mice before testing PRI mice. The data indicated that viruses may overcome host resistance by variants which kill at low levels of viral multiplication or which are not inhibited by the multiplication-depressing factor.