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

导致狂犬病病毒神经毒力的病毒和宿主因素。

基本信息

批准号：
08456150
负责人：
MINAMOTO Nobuyuki
金额：
$ 4.29万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08456150/
关键词：
Rabies virus Glycoprotein gene Nucleotide substitution Revertant Deduced amino acid sequence Whole-cell patch clamp Na^+ channel Ultra structure 糖(G)遺伝子

项目摘要

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.

本研究通过对狂犬病病毒神经毒力的分子基础的研究，对病毒粒子和细胞内的致病因子进行了分析和表征。结果如下：1）对成年小鼠无致死能力的RC-HL株在乳鼠脑内传代22次。2）获得部分毒力的回复突变株G蛋白和M蛋白各有一个氨基酸替换。与RC-HL株全基因组相比，M基因3 ′端非编码区有一个核苷酸替换。这些改变的一个核苷酸和两个氨基酸的位置可能是小鼠毒力所必需的。3）在具有细胞融合抑制活性的病毒中和单克隆抗体（N-MAb）存在下选择的抗原变体的比较分析，揭示了融合活性对应于G蛋白35位的胱氨酸。4）通过N-单克隆抗体识别的氨基酸位置333的（3）与狂犬病病毒毒力相关的蛋白质不能从强毒西原株中选出，表明该位置的精氨酸是强毒狂犬病毒复制所必需的。结果表明，狂犬病毒感染小鼠神经母细胞瘤NA细胞后，Na^+电流和延迟整流K^<1+>电流离子通道功能表达降低，并为狂犬病发病机制中可能涉及膜特性的改变提供了证据。