H9N2 virus-derived M1 protein promotes H5N6 virus release in mammalian cells: Mechanism of avian influenza virus inter-species infection in humans

• Published in: PLoS pathogens 2021-12, Vol.17 (12), p.e1010098-e1010098
• Main Authors: Li, Fangtao, Liu, Jiyu, Yang, Jizhe, Sun, Haoran, Jiang, Zhimin, Wang, Chenxi, Zhang, Xin, Yu, Yinghui, Zhao, Chuankuo, Pu, Juan, Sun, Yipeng, Chang, Kin-Chow, Liu, Jinhua, Sun, Honglei
• Format: Article
• Language: English
• Subjects: Animals; Avian flu; Avian influenza; Avian influenza viruses; Binding; Biology and Life Sciences; Budding; Cell lines; Cell membranes; Chickens - virology; Disease transmission; Distribution; Genes; Genetic aspects; Genetic crosses; HA protein; Health aspects; Health risks; Hemagglutinins; Humans; Infections; Influenza; Influenza A virus - genetics; Influenza A Virus, H9N2 Subtype - genetics; Influenza in Birds - virology; Influenza, Human - virology; Localization; Mammalian cells; Mammals; Matrix protein; Medicine and Health Sciences; Microscopy; Phylogenetics; Phylogeny; Physiological aspects; Poultry; Progeny; Protein transport; Proteins; Public health; Reassortant Viruses - genetics; Research and Analysis Methods; Viral Matrix Proteins - metabolism; Viral proteins; Viral Zoonoses - virology; Virus Release; Virus-like particles; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010098

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.