Basler C F, Reid A H, Dybing J K, Janczewski T A, Fanning T G, Zheng H, Salvatore M, Perdue M L, Swayne D E, García-Sastre A, Palese P, Taubenberger J K
Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2746-51. doi: 10.1073/pnas.031575198.
The influenza A virus pandemic of 1918-1919 resulted in an estimated 20-40 million deaths worldwide. The hemagglutinin and neuraminidase sequences of the 1918 virus were previously determined. We here report the sequence of the A/Brevig Mission/1/18 (H1N1) virus nonstructural (NS) segment encoding two proteins, NS1 and nuclear export protein. Phylogenetically, these genes appear to be close to the common ancestor of subsequent human and classical swine strain NS genes. Recently, the influenza A virus NS1 protein was shown to be a type I IFN antagonist that plays an important role in viral pathogenesis. By using the recently developed technique of generating influenza A viruses entirely from cloned cDNAs, the hypothesis that the 1918 virus NS1 gene played a role in virulence was tested in a mouse model. In a BSL3+ laboratory, viruses were generated that possessed either the 1918 NS1 gene alone or the entire 1918 NS segment in a background of influenza A/WSN/33 (H1N1), a mouse-adapted virus derived from a human influenza strain first isolated in 1933. These 1918 NS viruses replicated well in tissue culture but were attenuated in mice as compared with the isogenic control viruses. This attenuation in mice may be related to the human origin of the 1918 NS1 gene. These results suggest that interaction of the NS1 protein with host-cell factors plays a significant role in viral pathogenesis.
1918 - 1919年的甲型流感病毒大流行在全球造成了约2000万至4000万人死亡。1918年病毒的血凝素和神经氨酸酶序列此前已被确定。我们在此报告A/布雷维格米申/1/18（H1N1）病毒非结构（NS）片段的序列，该片段编码两种蛋白质，即NS1和核输出蛋白。从系统发育角度看，这些基因似乎与后续人类和经典猪株NS基因的共同祖先相近。最近，甲型流感病毒NS1蛋白被证明是一种I型干扰素拮抗剂，在病毒发病机制中起重要作用。通过使用最近开发的完全从克隆cDNA产生甲型流感病毒的技术，在小鼠模型中测试了1918年病毒NS1基因在毒力方面发挥作用的假说。在一个生物安全3级加强实验室中，产生了仅拥有1918年NS1基因或在甲型流感病毒A/WSN/33（H1N1）背景下拥有完整1918年NS片段的病毒，A/WSN/33（H1N1）是一种源自1933年首次分离的人类流感毒株的小鼠适应病毒。这些1918年NS病毒在组织培养中复制良好，但与同基因对照病毒相比，在小鼠中减毒。这种在小鼠中的减毒可能与1918年NS1基因的人类起源有关。这些结果表明，NS1蛋白与宿主细胞因子的相互作用在病毒发病机制中起重要作用。
