Introduction of Virulence Markers in PB2 of Pandemic Swine-Origin Influenza Virus Does Not Result in Enhanced Virulence or Transmission
Introduction of Virulence Markers in PB2 of Pandemic Swine-Origin Influenza Virus Does Not Result in Enhanced Virulence or Transmission
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DOI：
10.1128/jvi.02634-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Fouchier, Ron A. M.
中科院分区：
文献类型：
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作者：
Herfst, Sander;Chutinimitkul, Salin;Fouchier, Ron A. M.
在H1N1猪源流感病毒（S-OIV）大流行的前6个月，绝大多数感染相对较轻。据推测，病毒基因组的突变可能导致更致命的病毒，导致更严重的大流行。PB 2蛋白中的突变E627 K和D 701 N先前已被鉴定为哺乳动物中禽流感和大流行性流感病毒毒力的决定因素。这些突变在2009年大流行早期检测到的S-OIV中不存在。在此，使用反向遗传学，将突变E627 K、D 701 N和E677 G引入原型S-OIV A/Netherlands/602/2009，并研究它们对病毒复制、毒力和传播的影响。突变E627 K和D 701 N引起由S-OIV聚合酶复合物驱动的报告基因表达增加。三种突变均不影响病毒在体外的复制。这些突变对小鼠和雪貂呼吸道中的病毒复制或发病机制没有重大影响。这三种变异病毒都是通过雪貂的气溶胶或呼吸道飞沫传播的。因此，在当前S-OIV的背景下，PB 2中关键的已知毒力标志物的影响令人惊讶地小。这项研究并不排除未来出现其他与毒力相关突变的S-OIV的可能性。我们的结论是，监测研究，旨在检测S-OIV的毒力增加或传播不应该仅仅依赖于毒力标记物在过去确定的，但应包括病毒表型的详细表征，在人类严重病例中检测到的病毒的遗传特征的指导下。
In the first 6 months of the H1N1 swine-origin influenza virus (S-OIV) pandemic, the vast majority of infections were relatively mild. It has been postulated that mutations in the viral genome could result in more virulent viruses, leading to a more severe pandemic. Mutations E627K and D701N in the PB2 protein have previously been identified as determinants of avian and pandemic influenza virus virulence in mammals. These mutations were absent in S-OIVs detected early in the 2009 pandemic. Here, using reverse genetics, mutations E627K, D701N, and E677G were introduced into the prototype S-OIV A/Netherlands/602/2009, and their effects on virus replication, virulence, and transmission were investigated. Mutations E627K and D701N caused increased reporter gene expression driven by the S-OIV polymerase complex. None of the three mutations affected virus replication in vitro. The mutations had no major impact on virus replication in the respiratory tracts of mice and ferrets or on pathogenesis. All three mutant viruses were transmitted via aerosols or respiratory droplets in ferrets. Thus, the impact of key known virulence markers in PB2 in the context of current S-OIVs was surprisingly small. This study does not exclude the possibility of emergence of S-OIVs with other virulence-associated mutations in the future. We conclude that surveillance studies aimed at detecting S-OIVs with increased virulence or transmission should not rely solely on virulence markers identified in the past but should include detailed characterization of virus phenotypes, guided by genetic signatures of viruses detected in severe cases of disease in humans.