Viral and host factors contributing to the neuro-virulence of rabies virus.

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In this study, to definite the molecular bases of neurovirulence in rabies virus, we have analyzed and characterized the pathogenic factors in the both virion and cells. The results run as follows :1) The RC-HL strain lacking the capacity to kill adult mice was passaged intracerebrally 22 times in suckling mice. Each passaged virus failed to regain lethal virulence for adult mice, although the viruses were increased to level of mouse pathogenicity.2) The revertant strain acquired partially virulence had each one amino acid substitution in G and M proteins. and one nucleotide substitution in non-coding region of 3' end in M gene when compared with full genome of the RC-HL strain. These changed positions of a nucleotide and two amino acids may necessary for mouse virulence.3) A comparative analysis of antigenic variants selected in the presence of virus-neutralizing monoclonal antibody (N-MAb) with cell-fusion inhibition activity, revealed that fusion activity corresponded to cystine at position 35 of the G protein.4) Any neutralization-resistant mutants by a N-MAb recognized an amino acid at position 333 of the (3 protein that related to virulence of rabies virus could not be selected from virulent virus, the Nishigahara strain, suggesting that arginine at the position is necessary for replication of virulent rabies virus.5) It was suggested that infection of mouse neuroblastoma NA cells with rabies virus causes reduction of functional expression of ion channels responsible for Na^+ current and delayed rectifier K^<1+> current, and provided evidence for possible involvement of the change in membrane properties in the pathogenesis of rabies disease.