Kobasa Darwyn, Takada Ayato, Shinya Kyoko, Hatta Masato, Halfmann Peter, Theriault Steven, Suzuki Hiroshi, Nishimura Hidekazu, Mitamura Keiko, Sugaya Norio, Usui Taichi, Murata Takeomi, Maeda Yasuko, Watanabe Shinji, Suresh M, Suzuki Takashi, Suzuki Yasuo, Feldmann Heinz, Kawaoka Yoshihiro
Department of Pathobiological Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
Nature. 2004 Oct 7;431(7009):703-7. doi: 10.1038/nature02951.
The 'Spanish' influenza pandemic of 1918-19 was the most devastating outbreak of infectious disease in recorded history. At least 20 million people died from their illness, which was characterized by an unusually severe and rapid clinical course. The complete sequencing of several genes of the 1918 influenza virus has made it possible to study the functions of the proteins encoded by these genes in viruses generated by reverse genetics, a technique that permits the generation of infectious viruses entirely from cloned complementary DNA. Thus, to identify properties of the 1918 pandemic influenza A strain that might be related to its extraordinary virulence, viruses were produced containing the viral haemagglutinin (HA) and neuraminidase (NA) genes of the 1918 strain. The HA of this strain supports the pathogenicity of a mouse-adapted virus in this animal. Here we demonstrate that the HA of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host. Moreover, these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and induce high levels of macrophage-derived chemokines and cytokines, which resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic.
1918年至1919年的“西班牙”流感大流行是有记录以来最具毁灭性的传染病疫情。至少2000万人因病死亡，其特点是临床病程异常严重且迅速。对1918年流感病毒的几个基因进行全序列测序，使得研究这些基因编码的蛋白质在通过反向遗传学产生的病毒中的功能成为可能，反向遗传学是一种能完全从克隆的互补DNA产生感染性病毒的技术。因此，为了确定1918年大流行甲型流感病毒株可能与其异常毒力相关的特性，制备了含有1918年毒株的病毒血凝素（HA）和神经氨酸酶（NA）基因的病毒。该毒株的HA支持一种适应小鼠的病毒在这种动物中的致病性。在此，我们证明1918年病毒的HA赋予近期人类病毒在小鼠中更强的致病性，而这些人类病毒在该宿主中原本是无致病性的。此外，这些表达1918年病毒HA的高毒力重组病毒可感染整个肺部，并诱导高水平的巨噬细胞衍生趋化因子和细胞因子，这导致炎症细胞浸润和严重出血，这是原始大流行期间所产生疾病的特征。
