Key result
The introduction of MVV mutations (I66M, I109V, I133V) into a prototypic avian PB2 gene increased viral replication in mammalian hosts and served as an essential prerequisite for acquiring fatal mammalian pathogenic mutations.
The acquisition of MVV mutations in the avian PB2 gene increases viral replication and serves as a structural prerequisite for influenza A virus to acquire fatal mammalian pathogenicity.
MVV mutations may mark early mammalian adaptation in avian influenza; leaves open human pathogenicity risk and surveillance utility.
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.
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Lee et al. (2017) studied Influenza A virus infection. MVV mutations (I66M, I109V, I133V) in PB2 gene vs. Wild-type prototypic avian PB2 gene (01310) was evaluated on Viral replication efficiency and mammalian pathogenicity (body weight loss and mortality in mice). The introduction of MVV mutations (I66M, I109V, I133V) into a prototypic avian PB2 gene increased viral replication in mammalian hosts and served as an essential prerequisite for acquiring fatal mammalian pathogenic mutations.
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