Neurovirulence in mice of soluble receptor-resistant (srr) mutants of mouse hepatitis virus: intensive apoptosis caused by less virulent srr mutant

Three soluble receptor-resistant (srr) mutants, srr7, srr11 and srr18, deri ved from a highly neurotropic mouse hepatitis virus (MHV) JHMV have a singl e amino acid mutation in the spike (S) protein. We examined using ICR mice whether the amino acids mutated in the mutants were involved in the neurovi rulence. Srr7 showed apparently reduced neurovirulence relative to the wild type (wt) JHMV in terms of the LD50 and survival time, while the others sho wed slightly reduced virulence. In the brain and spinal cord, the growth of srr7 was more than 2 log(10) lower than that of the wt virus. Histopatholo gically, no significant difference was revealed between wt and srr7-infecte d mice on day 2 postinoculation (p.i.), with only scant inflammation and a minimum degree of neuropathological changes. The major difference was that apoptotic cells were frequently encountered in the srr7-infected mouse brai n, but not in wt-infected mice on day 2 p.i. However, there was no differen ce between these viruses in the potential to induce apoptosis in cultured c ells. The apoptosis in the brain did not appear to result from the direct v iral attack, since apoptotic cells were found in the lesion where viral ant igens were barely detected. The present study suggests that the amino acids mutated in the S protein of srr mutants, especially the amino acid at posi tion 1114 mutated in srr7, influence the neurovirulence in mice.