Neurovirulent strains of Alphavirus induce apoptosis in bcl-2-expressing cells: role of a single amino acid change in the E2 glycoprotein.
Neurovirulent strains of Alphavirus induce apoptosis in bcl-2-expressing cells: role of a single amino acid change in the E2 glycoprotein.
复制标题
甲病毒的神经毒株诱导 bcl-2 表达细胞凋亡：E2 糖蛋白中单个氨基酸变化的作用。
DOI：
10.1073/pnas.91.11.5202
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发表时间：
1994
影响因子：
11.1
通讯作者：
Hardwick,JM
中科院分区：
文献类型：
--
作者：
Ubol,S;Tucker,PC;Griffin,DE;Hardwick,JM
对脊髓灰质炎病毒、阿尔法病毒、疱疹病毒、免疫缺陷病毒和其他病毒的无毒株和神经毒株的分离和序列比较已经确定了导致神经系统疾病所需的基因变化。这些基因变化导致神经毒力的分子机制尚不清楚。实验室中一种无毒的甲型病毒辛德比斯毒株不是通过致命性寄生杀死大多数培养的细胞系，而是通过诱导细胞凋亡或程序性细胞死亡。将人bcl2癌基因导入培养细胞，可以阻断Sindbis病毒诱导的细胞凋亡，导致持续的病毒感染，类似于在免疫缺陷小鼠的脑中观察到的情况。我们研究了辛德比斯病毒神经毒株可以克服bcl2保护作用的可能性--这是解释这些毒株导致致命疾病的能力的潜在机制。辛德比斯病毒株对2到4周大的小鼠是致命的，尽管存在bcl2，但还是诱导了培养细胞的凋亡性死亡。利用重组病毒，我们证明了辛德比斯病毒E2糖蛋白中的一个单一氨基酸的变化既赋予了神经毒力，又赋予了杀死表达bcl2的细胞的能力。
The isolation and sequence comparison of avirulent and neurovirulent strains of polio virus, alpha virus, herpes virus, immunodeficiency virus, and other viruses have identified genetic changes that are required to cause disease in the nervous system. The molecular mechanisms by which these genetic changes result in neurovirulence are unknown. An avirulent laboratory strain of the Alphavirus Sindbis kills most cultured cell lines not by lethal parasitism, but by inducing apoptosis or programmed cell death. Transfection of cultured cells with the human bcl-2 oncogene can block Sindbis virus-induced apoptosis, resulting in a persistent viral infection resembling that observed in brains of immunodeficient mice. We investigated the possibility that neurovirulent strains of Sindbis virus could overcome the protective effects of bcl-2--a potential mechanism to explain the ability of these strains to cause fatal disease. Strains of Sindbis virus that were lethal for 2- to 4-week-old mice induced apoptotic death in cultured cells despite the presence of bcl-2. Using recombinant viruses, we show that a single amino acid change in the E2 glycoprotein of Sindbis virus confers both neurovirulence and the ability to kill cells expressing bcl-2.