J. Craig Venter Institute, Rockville, Maryland, United States of America.
PLoS One. 2013 Jun 14;8(6):e67616. doi: 10.1371/journal.pone.0067616. Print 2013.
The 2009/2010 pandemic influenza virus (H1N1pdm) contains an avian-lineage PB2 gene that lacks E627K and D701N substitutions important in the pathogenesis and transmission of avian-origin viruses in humans or other mammals. Previous studies have shown that PB2-627K is not necessary because of a compensatory Q591R substitution. The role that PB2-701N plays in the H1N1pdm phenotype is not well understood. Therefore, PB2-D701N was introduced into an H1N1pdm virus (A/New York/1682/2009 (NY1682)) and analyzed in vitro and in vivo. Mini-genome replication assay, in vitro replication characteristics in cell lines, and analysis in the mouse and ferret models demonstrated that PB2-D701N increased virus replication rates and resulted in more severe pathogenicity in mice and more efficient transmission in ferrets. In addition, compared to the NY1682-WT virus, the NY1682-D701N mutant virus induced less IFN-λ and replicated to a higher titer in primary human alveolar epithelial cells. These findings suggest that the acquisition of the PB2-701N substitution by H1N1pdm viruses may result in more severe disease or increase transmission in humans.
2009/2010 年大流行性流感病毒（H1N1pdm）含有一个禽源谱系的 PB2 基因，该基因缺乏在人类或其他哺乳动物中对禽源病毒的发病机制和传播很重要的 E627K 和 D701N 取代。先前的研究表明，由于存在补偿性 Q591R 取代，PB2-627K 不是必需的。PB2-701N 在 H1N1pdm 表型中的作用尚不清楚。因此，将 PB2-D701N 引入 H1N1pdm 病毒（A/New York/1682/2009（NY1682））中，并进行了体外和体内分析。迷你基因组复制试验、细胞系中的体外复制特征以及小鼠和雪貂模型中的分析表明，PB2-D701N 增加了病毒复制率，导致小鼠的致病性更严重，雪貂中的传播效率更高。此外，与 NY1682-WT 病毒相比，NY1682-D701N 突变病毒在原代人肺泡上皮细胞中诱导的 IFN-λ 较少，复制滴度更高。这些发现表明，H1N1pdm 病毒获得 PB2-701N 取代可能导致更严重的疾病或增加在人类中的传播。
