Mouse hepatitis virus type 4 (JHM strains). induced fatal central nervous system disease. I. genetic control and murine neuron as the susceptible site of disease

The evidence for genetic control was obtained using inbred mouse strains, F1 and Fz mice generated from crossing susceptible and resistant mice, and mice obtained by backcrossing the FI mice to both susceptible and resistant parental strains. O f the eleven inbred strains studied, only one, S j L / j , was resistant to the effects of MHV-4 after intracerebral inoculation. The complete susceptibility of BALB/c mice and of the Ft hybrids obtained from mating BALB/c × SJL/J indicates that resistance of MHV-4 is recessive. Mortality data obtained both from F2 intercrosses and from FI backcrosses to each parent best fit a single recessive gene model (Table II) . It should be emphasized that these results were obtained with 4-wk-old mice, a time when neurons are mature. Complementary data was obtained from in vitro studies when neurons from B A L B / W E H I and the F1 hybrids obtained from mating B A L B / W E H I × S J L / J mice produced 4 logs more infectious virus than similarly prepared neurons from SJL/J mice (Table V) . Several investigators have studied host factors affecting resistance to other strains of MHV. The pioneering work of Bang et al. (23) (24) (25) (26) (27) (28) focused on the nature of susceptibility to MHV-2 in causing fatal hepatitis in PRI mice but not in C3H mice. These investigators showed that the ability of virus to replicate in vitro in macrophages correlated with production of fatal hepatitis and that resistance was inherited as a single autosomal recessive gene. Our studies complement and extend those of Bang by showing that MHV-4 resistance at the host level, like MHV-2, seem to be inherited as a single autosomal recessive gene. The apparent difference between MHV-2 and MHV-4 lies in the primary target tissue injured by viral replication--the former is liver cells and the latter, neurons. Interestingly, although replication of MHV-2 is restricted in macrophages from C3H mice (23, 26) , macrophages from C3H mice are susceptible to replication of MHV-3 (29) and MHV-4 in vitro (R. Knobler and M. B.