PB2-Q591K Mutation Determines the Pathogenicity of Avian H9N2 Influenza Viruses for Mammalian Species.

Congrong Wang,Zi Feng Yang,Chris Ka Pun Mok,Zhi Zhang,Horace Hok Yeung Lee,Stefan Pöhlmann

doi:10.1371/journal.pone.0162163

Abstract

BackgroundInfluenza A subtype H9N2 is widespread and prevalent in poultry. It has repeatedly transmitted zoonotically to cause mild influenza-like illness in humans and is regarded as a potential pandemic candidate. In additon, the six internal genes of H7N9 and H10N8 viruses which caused infection in human in China as well as some of the highly pathogenic H5N1 strains are origined from H9N2. Previous studies have shown that the mammalian adaptation PB2-Q591K contributes to the pathogenicity of H5N1 and H7N9 viruses. However, the role of the PB2-Q591K mutation in H9N2 subtype is still not well understood.MethodsTo define and compare the individual role of PB2-Q591K substitution in the PB2 gene segment of H9N2 in relation to polymerase activity, replication competence and the pathogenicity using in vitro and in vivo models.ResultsThe PB2-Q591K mutation in H9N2 virus enhanced the polymerase activity and virus replication in human NHBE cells when compared to the wild type strain. Mice infected with the PB2 mutant showed significant weight loss, higher virus replication and immune responses in the lungs.ConclusionsOur evidences suggest that the PB2-Q591K, in addition to the -E627K mutation in H9N2 enhanced the pathogenicity in mammalian host.

Highlights

Influenza A subtype H9N2 viruses are the most widespread and prevalent influenza viruses in poultry found in Asia
The PB2-Q591K mutation in H9N2 virus enhanced the polymerase activity and virus replication in human Normal Human Bronchial Epithelial (NHBE) cells when compared to the wild type strain
Our evidences suggest that the PB2-Q591K, in addition to the -E627K mutation in H9N2 enhanced the pathogenicity in mammalian host

Summary

Introduction

Influenza A subtype H9N2 viruses are the most widespread and prevalent influenza viruses in poultry found in Asia. The impact of H9N2 subtypes has been known to influence the human health through two pathways: On one hand, the 2+6 (2 surface genes + 6 internal genes) recombination was repeatedly found in the H5N1, H7N9 and H10N8 outbreaks in human being In these outbreaks, the six internal genes of H9N2 viruses were found to combine with the HA and NA genes of other subtypes resulting to new virus strains and subsequently caused pathogenicity in human. Our previous study found that two amino acids residues located at the position 253 and 591 of the H9N2 PB2 gene were mutated after serial passages in mammalian cells while all other gene segments being unaffected [14] The virus with both D253N and Q591K mutations in its PB2 showed higher cytokine induction and replication phenotype in our human cell models. The role of the PB2-Q591K mutation in H9N2 subtype is still not well understood

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Conclusion