Synergistic effect of PB2 283M and 526R contributes to enhanced virulence of H5N8 influenza viruses in mice

Xiao Wang,Tao Qin,Siwen Zheng,Xiufan Liu,Xixin Zha,Dandan Wang,Sujuan Chen,Wenjun Ma,Daxin Peng

doi:10.1186/s13567-017-0471-0

Abstract

Highly pathogenic avian influenza (HPAI) H5N8 virus has caused considerable economic losses to poultry industry and poses a great threat to public health. Our previous study revealed two genetically similar HPAI H5N8 viruses displaying completely different virulence in mice. However, the molecular basis for viral pathogenicity to mammals remains unknown. Herein, we generated a series of reassortants between the two viruses and evaluated their virulence in mice. We demonstrated that 283M in PB2 is a new mammalian virulence marker for H5 viruses and that synergistic effect of amino acid residues 283M and 526R in PB2 is responsible for high virulence of the HPAI H5N8 virus. Analysis of available PB2 sequences showed that PB2 283M is highly conserved among influenza A viruses, while PB2 526R presents in most of human H3N2 and H5N1 isolates. Further study confirmed that the residues 283M and 526R had similar impacts on an HPAI H5N1 virus, suggesting that influenza viruses with both residues may replicate well in mammalian hosts. Together, these results present new insights for synergistic effect of 283M and 526R in PB2 of H5 HPAI virus on virulence to mammalian host, furthering our understanding of the pathogenesis of influenza A virus.

Highlights

Since H5N1 highly pathogenic avian influenza (HPAI) virus was first detected from sick goose in Guangdong province in China in 1996, the HPAI H5N1 virus has caused huge economic loss for poultry industry worldwide, and infected more than 850 humans since 2003 with approximately 50% fatality rate [1], which has been considered as one of candidates to cause the human pandemic [2, 3]
Through comparing to other highly- and low-virulent avian influenza virus strains, we speculated that the substitutions G195D and I283M in PB2, V339I in PB1, V194I and L422I in HA most likely contribute to the high virulence of the CZ virus in mice [42]
We have identified the PB2 crucial for difference of virulence in mice between HPAI CZ and JY H5N8 viruses (Figure 2A), and further pinpointed synergistic effect of amino acid residues 283M and 526R in the PB2 responsible for the high virulence of Figure 6 virulence of HPAI H5N1 S and its mutated viruses in mice

Summary

Introduction

Since H5N1 highly pathogenic avian influenza (HPAI) virus was first detected from sick goose in Guangdong province in China in 1996, the HPAI H5N1 virus has caused huge economic loss for poultry industry worldwide, and infected more than 850 humans since 2003 with approximately 50% fatality rate [1], which has been considered as one of candidates to cause the human pandemic [2, 3]. In late 2013 and early 2014, an HPAI H5N8 virus belonging to the clade 2.3.4.4 of the A/goose/Guangdong/1/1996 lineage caused a large outbreak in domestic poultry in South Korea [4]. The HPAI H5N8 virus was detected in birds in Asian and European countries and outbreaks in domestic poultry caused by this virus have been reported in. Outbreaks of HPAI H5N8 virus have caused significant economic losses to the poultry industry, and more importantly, its potential threat to public health cannot be neglected

Methods

Results

Conclusion