Laboratory of Avian Diseases, College of Veterinary Medicine, Seoul National University, 08826, Seoul, Republic of Korea.
Division of Antimicrobial Resistance, Center for Infectious Diseases, National Research Institute of Health, KCDC, Cheongju, Republic of Korea.
Sci Rep. 2017 Aug 31;7(1):10205. doi: 10.1038/s41598-017-09560-z.
The polymerase of avian influenza A virus (AIV) is a heterotrimer composed of PB2, PB1, and PA. PB2 plays a role in overcoming the host barrier; however, the genetic prerequisites for avian PB2 to acquire mammalian pathogenic mutations have not been well elucidated. Previously, we identified a prototypic avian PB2 that conferred non-replicative and non-pathogenic traits to a PR8-derived recombinant virus when it was used to infect mice. Here, we demonstrated that key amino acid mutations (I66M, I109V, and I133V, collectively referred to as MVV) of this prototypic avian PB2 increase the replication efficiency of recombinant PR8 virus carrying the mutated PB2 in both avian and mammalian hosts. The MVV mutations caused no weight loss in mice, but they did allow replication in infected lungs, and the viruses acquired fatal mammalian pathogenic mutations such as Q591R/K, E627K, or D701N in the infected lungs. The MVV mutations are located at the interfaces of the trimer and are predicted to increase the strength of this structure. Thus, gaining MVV mutations might be the first step for AIV to acquire mammalian pathogenicity. These results provide new insights into the evolution of AIV in birds and mammals.
禽流感病毒 (AIV) 的聚合酶是由 PB2、PB1 和 PA 组成的异三聚体。PB2 在克服宿主屏障方面发挥作用；然而，禽流感 PB2 获得哺乳动物致病突变的遗传前提尚未得到很好的阐明。先前，我们鉴定了一个典型的禽 PB2，当它被用于感染小鼠时，赋予了源自 PR8 的重组病毒非复制和非致病性特征。在这里，我们证明了这个典型禽 PB2 的关键氨基酸突变（I66M、I109V 和 I133V，统称为 MVV）增加了携带突变 PB2 的重组 PR8 病毒在禽类和哺乳动物宿主中的复制效率。MVV 突变不会导致小鼠体重减轻，但它们确实允许在感染的肺部中复制，并且病毒在感染的肺部中获得了致命的哺乳动物致病突变，如 Q591R/K、E627K 或 D701N。MVV 突变位于三聚体的界面上，预计会增加该结构的强度。因此，获得 MVV 突变可能是 AIV 获得哺乳动物致病性的第一步。这些结果为 AIV 在鸟类和哺乳动物中的进化提供了新的见解。
