APOPTOSIS--MECHANISM OF CELL KILLING BY INFLUENZA VIRUS

该项目的长期目标是通过以下方式定义分子机制： A型流感病毒会杀死细胞。 甲型流感病毒继续 在人类、低等哺乳动物和鸟类中引起严重的疾病问题; 然而，这些病毒杀死宿主细胞的机制仍然存在， 未定义。 我们自己的研究集中在一个鸟类模型上， 使用高毒株A/Ty/Ont/7732/66的流感发病机理 (Ty/Ont），迅速在鸟类中产生毁灭性疾病，包括 严重的淋巴衰竭 我们最近的研究表明，Ty/Ont 在鸡淋巴细胞系中复制并诱导凋亡， 反映了体内感染。 我们将这些研究扩展到 哺乳动物系统，并发现人类病毒，A/PR/8/34（PR/8）， 以及Ty/Ont和其他流感病毒株，诱导细胞凋亡， 哺乳动物细胞系，Madin-Darby犬肾（MDCK）。 这些发现 表明细胞凋亡是流感病毒诱导细胞凋亡的一般机制 细胞死亡 为了支持这一观点，我们的初步研究表明， 这些病毒引起的细胞凋亡被bcl-2阻止， 参与抑制细胞凋亡的癌基因。 具体目标是： 1.检查流感病毒诱导的细胞通路 凋亡 2.确定特定流感病毒基因在细胞凋亡中的作用。 3.定义参与体内细胞凋亡的病毒基因的特定区域 和体外培养。 通过实现这些具体目标获得的信息将确定 特定细胞和病毒基因在细胞死亡中的作用。 这提供 这是一个获得基本信息的独特机会， 流感病毒的发病机制以及细胞凋亡。

The long term goal of this project is to define molecular mechanisms by which influenza A viruses kill cells. Influenza A viruses continue to cause significant disease problems in humans, lower mammals and birds; however, the mechanism(s) by which these viruses kill host cells remains undefined. Our own studies have focused on an avian model to examine influenza pathogenesis, using a highly virulent strain, A/Ty/Ont/7732/66 (Ty/Ont) which rapidly produces devastating disease in birds, including severe lymphoid depletion. Our recent studies demonstrate that Ty/Ont replicates and induces apoptosis in a chicken lymphocyte cell line, reflective of the in vivo infection. We extended these studies to the mammalian system and discovered that the human virus, A/PR/8/34 (PR/8), as well as Ty/Ont and other influenza strains, induces apoptosis in the mammalian cell line, Madin-Darby canine kidney (MDCK). These findings suggest that apoptosis is a general mechanism of influenza virus-induced cell death. In support of this idea, our preliminary studies indicate that apoptosis by these viruses is prevented by bcl-2, a cellular oncogene involved in suppressing apoptosis. The specific aims are to: 1. Examine the cellular pathways involved in influenza virus-induced apoptosis. 2. Determine the role of specific influenza viral genes in apoptosis. 3. Define specific regions of viral gene(s) involved in apoptosis in vivo and in vitro. The information gained from addressing these specific aims will identify the role of specific cellular and viral genes in cell death. This offers a unique opportunity to obtain information basic to understanding influenza virus pathogenesis, as well as apoptosis.