Rank orders of mammalian pathogenicity-related PB2 mutations of avian influenza A viruses

Chung-Young Lee,Youn-Jeong Lee,Se-Hee An,Jun-Gu Choi,Hyuk-Joon Kwon,Jae-Hong Kim

doi:10.1038/s41598-020-62036-5

Chung-Young Lee, Youn-Jeong Lee + Show 4 more

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https://doi.org/10.1038/s41598-020-62036-5

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Abstract

The PB2 gene is one of the key determinants for the mammalian adaptation of avian influenza A viruses (IAVs). Although mammalian pathogenicity-related mutations (MPMs) in PB2 genes were identified in different genetic backgrounds of avian IAVs, the relative effects of single or multiple mutations on viral fitness could not be directly compared. Furthermore, their mutational steps during mammalian adaptation had been unclear. In this study, we collectively compared the effects of individual and combined MPMs on viral fitness and determined their rank orders using a prototypic PB2 gene. Early acquired mutations may determine the function and potency of subsequent mutations and be important for recruiting multiple, competent combinations of MPMs. Higher mammalian pathogenicity was acquired with the greater accumulation of MPMs. Thus, the rank orders and the prototypic PB2 gene may be useful for predicting the present and future risks of PB2 genes of avian and mammalian IAVs.

Highlights

Waterfowl are reservoirs for influenza A viruses (IAVs), and close interaction between waterfowl and other animals causes occasional cross species transmission to result in successful settle-down by acquiring host adaptive mutations in their eight segmented genomes (PB2, PB1, PA, HA, NP, NA, M, and NS)[1]
Many mammalian pathogenicity-related mutations (MPMs, D9N, I147T (SIB-2-3). Although SIB-3 (I147T), E158G, E192K, A199S, D253N, T271A, K339T, F404L, K526R, A588I, A588T, G590S, Q591R, Q591K, E627K, A674T, D701N, K702R, and S714R, etc.) in PB2 have been reported in different domains of the PB2 protein[3,4,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]
We classified them into 5 categories, Bird, Bird-Human [avian IAVs isolated form humans (H5, H6, H7, H9, and H10 IAVs)], Pig, pdmH1N1 (H1N1 IAVs during 2009 pandemic), and Human, and calculated the frequencies of their MPMs

Summary

Introduction

Waterfowl are reservoirs for influenza A viruses (IAVs), and close interaction between waterfowl and other animals causes occasional cross species transmission to result in successful settle-down by acquiring host adaptive mutations in their eight segmented genomes (PB2, PB1, PA, HA, NP, NA, M, and NS)[1]. The E627K mutation most potently increases polymerase activity, replication efficiency and pathogenicity of avian IAVs in mammalian hosts[3,4,17]. Human and swine IAVs possess already multiple MPMs, but their effects on mammalian pathogenicity have never been compared collectively. We found a prototypic avian PB2 gene (01310 PB2) that completely attenuated PR8-derived recombinant virus (7 + 1 reassortant) in mice and did not possess any MPMs except 661A and 683T, and identified the minimum essential mutations (I66M, I109V, and I133V, MVV mutations) to acquire additional MPMs such as Q591R/K, E627K, and D701N29,30. We compared polymerase activities of the hypothetical intermediate and final combinations of MPMs acquired during adaptation to pigs and humans and generated PR8-derived recombinant viruses possessing major combinations of MPMs to compare their effects on viral replication efficiency and pathogenicity in mammalian hosts

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