Morimoto K, Hooper D C, Spitsin S, Koprowski H, Dietzschold B
Center for Neurovirology, Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799, USA.
J Virol. 1999 Jan;73(1):510-8. doi: 10.1128/JVI.73.1.510-518.1999.
The mouse-adapted rabies virus strain CVS-24 has stable variants, CVS-B2c and CVS-N2c, which differ greatly in their pathogenicity for normal adult mice and in their ability to infect nonneuronal cells. The glycoprotein (G protein), which has previously been implicated in rabies virus pathogenicity, shows substantial structural differences between these variants. Although prior studies have identified antigenic site III of the G protein as the major pathogenicity determinant, CVS-B2c and CVS-N2c do not vary at this site. The possibility that pathogenicity is inversely related to G protein expression levels is suggested by the finding that CVS-B2c, the less pathogenic variant, expresses at least fourfold-higher levels of G protein than CVS-N2c in infected neurons. Although there is some difference between CVS-B2c- and CVS-N2c-infected neurons in G protein mRNA expression levels, the differential expression of G protein appears to be largely determined by posttranslational mechanisms that affect G protein stability. Pulse-chase experiments indicated that the G protein of CVS-B2c is degraded more slowly than that of CVS-N2c. The accumulation of G protein correlated with the induction of programmed cell death in CVS-B2c-infected neurons. The extent of apoptosis was considerably lower in CVS-N2c-infected neurons, where G protein expression was minimal. While nucleoprotein (N protein) expression levels were similar in neurons infected with either variant, the transport of N protein into neuronal processes was strongly inhibited in CVS-B2c-infected cells. Thus, downregulation of G protein expression in neuronal cells evidently contributes to rabies virus pathogenesis by preventing apoptosis and the apparently associated failure of the axonal transport of N protein.
适应小鼠的狂犬病病毒株CVS-24有稳定的变体CVS-B2c和CVS-N2c，它们对正常成年小鼠的致病性以及感染非神经元细胞的能力差异很大。此前已发现与狂犬病病毒致病性有关的糖蛋白（G蛋白）在这些变体之间存在显著的结构差异。尽管先前的研究已确定G蛋白的抗原位点III是主要的致病性决定因素，但CVS-B2c和CVS-N2c在该位点并无差异。致病性与G蛋白表达水平呈负相关这一可能性是由以下发现所提示的：致病性较低的变体CVS-B2c在受感染神经元中表达的G蛋白水平比CVS-N2c至少高四倍。尽管在CVS-B2c和CVS-N2c感染的神经元中G蛋白mRNA表达水平存在一些差异，但G蛋白的差异表达似乎在很大程度上是由影响G蛋白稳定性的翻译后机制所决定的。脉冲追踪实验表明，CVS-B2c的G蛋白降解速度比CVS-N2c的慢。G蛋白的积累与CVS-B2c感染的神经元中程序性细胞死亡的诱导相关。在G蛋白表达极少的CVS-N2c感染的神经元中，凋亡程度要低得多。虽然用这两种变体感染的神经元中核蛋白（N蛋白）表达水平相似，但在CVS-B2c感染的细胞中，N蛋白向神经突的转运受到强烈抑制。因此，神经元细胞中G蛋白表达的下调显然通过防止凋亡以及N蛋白轴突转运明显相关的失败而促进了狂犬病病毒的发病机制。
