Abstract
H5N6 highly pathogenic avian influenza virus (HPAIV) clade 2.3.4.4 not only exhibits unprecedented intercontinental spread in poultry, but can also cause serious infection in humans, posing a public health threat. Phylogenetic analyses show that 40% (8/20) of H5N6 viruses that infected humans carried H9N2 virus-derived internal genes. However, the precise contribution of H9N2 virus-derived internal genes to H5N6 virus infection in humans is unclear. Here, we report on the functional contribution of the H9N2 virus-derived matrix protein 1 (M1) to enhanced H5N6 virus replication capacity in mammalian cells. Unlike H5N1 virus-derived M1 protein, H9N2 virus-derived M1 protein showed high binding affinity for H5N6 hemagglutinin (HA) protein and increased viral progeny particle release in different mammalian cell lines. Human host factor, G protein subunit beta 1 (GNB1), exhibited strong binding to H9N2 virus-derived M1 protein to facilitate M1 transport to budding sites at the cell membrane. GNB1 knockdown inhibited the interaction between H9N2 virus-derived M1 and HA protein, and reduced influenza virus-like particles (VLPs) release. Our findings indicate that H9N2 virus-derived M1 protein promotes avian H5N6 influenza virus release from mammalian, in particular human cells, which could be a major viral factor for H5N6 virus cross-species infection.
Highlights
avian influenza viruses (AIVs) pose a constant threat to public health by regularly crossing host-species barriers to infect humans
Phylogenetic analysis of H5N6 viruses, using RAxML[33], found that the internal genes could be grouped into multiple genotypes based on the genetic reassortment with H5N1 virus, H9N2 virus, or waterfowl-origin low pathogenic avian influenza virus (LPAIV) (Figs 1A and S1 and S1 Table)
Further analysis showed that 11.7% (82/703) of H5N6 viruses circulating in poultry carried reassorted H9N2 virus-derived internal genes, while H5N6 viruses that infected humans carried reassorted H9N2 virusderived internal genes at 40.0% (8/20) (Fig 1B)
Summary
AIVs pose a constant threat to public health by regularly crossing host-species barriers to infect humans. H5N1 HPAIV has caused at least 863 reported human cases at around 53% mortality [1]. Since the first H5N6 virus infection in humans in China in 2014, there are to date 47 reported infections and 24 deaths[2]. H7N9 AIVs emerged in China in 2013 and subsequently caused five influenza epidemics[3]. Avian H9N2 viruses circulate globally through wild birds and are endemic in domestic poultry in China and elsewhere. Recent studies indicate that H9N2 viruses are capable of binding to the human-type sialic acid (SA) receptor and are transmissible among ferrets via respiratory droplets[4]. As of December 2020, at least 66 global cases of H9N2 infections in humans have been reported[5]
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