Pathogenicity and transmissibility of an H9N2 avian influenza virus that naturally harbors the mammalian-adaptive molecular factors in the hemagglutinin and PB2 proteins

A recent article by Gu in the Journal of Infection(1) reported two highly pathogenic H7N9 strains harboring the E627K mutation in the polybasic protein 2 (PB2) gene from chickens and showed that avian influenza viruses (AIVs) are evolving to adapt to humans. AIVs pose an important and ongoing threat to public health. Historically, both the highly pathogenic avian influenza viruses (H5N1, H5N6, H7N7, H7N3, and H7N9) and the lowly pathogenic avian influenza viruses (H7N2, H7N3, H9N2, H7N9, H6N1, H10N7, and H10N8) have caused sporadic human infections. Of these, H5N1, H5N6, H9N2, and H7N9 infections in humans continue today. Compared with the H5 and H7 viruses, the H9N2 virus is somehow neglected. However, H9N2 can donate its internal gene cassette to other AIV subtypes, such as H5N6, H7N9, and H10N8, which enhances their cross-species transmission ability and pathogenicity in mammals 2 Shen Y.Y. Ke C.W. Li Q. Yuan R.Y. Xiang D. Jia W.X. et al. Novel reassortant avian influenza A(H5N6) Viruses in Humans, Guangdong, China, 2015. Emerg Infect Dis. 2016; 22: 1507-1509 Crossref PubMed Scopus (49) Google Scholar , 3 Chen Y. Liang W. Yang S. Wu N. Gao H. Sheng J. et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet. 2013; 381: 1916-1925 Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar -–4 Chen H. Yuan H. Gao R. Zhang J. Wang D. Xiong Y. et al. Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet. 2014; 383: 714-721 Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar ; H9N2 can also directly infect humans. 5 Peiris M. Yuen K.Y. Leung C.W. Chan K.H. Ip P.L.S. Lai R.W.M. et al. Human infection with influenza H9N2. The Lancet. 1999; 354: 916-917 Abstract Full Text Full Text PDF PubMed Scopus (859) Google Scholar ,6 Yuan R. Liang L. Wu J. Kang Y. Song Y. Zou L. et al. Human infection with an avian influenza A/H9N2 virus in Guangdong in 2016. J Infect. 2017; 74: 422-425 Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Since the first human case reported in Hong Kong in 1999 5 Peiris M. Yuen K.Y. Leung C.W. Chan K.H. Ip P.L.S. Lai R.W.M. et al. Human infection with influenza H9N2. The Lancet. 1999; 354: 916-917 Abstract Full Text Full Text PDF PubMed Scopus (859) Google Scholar , 61 laboratory-confirmed human H9N2 infections have been reported 7 Influenza at the human-animal interface. https://www.who.int/influenza/human_animal_interface/HAI_Risk_Assessment/en/Accessed 7 August 2020[Internet]. 2020. Google Scholar . H9N2 virus infection in humans generally results in mild or asymptomatic illness and is often overlooked. Research based on extensive serological evidence showed particularly high seropositivity rates among poultry workers 8 Khan S.U. Anderson B.D. Heil G.L. Liang S. Gray G.C A systematic review and meta-analysis of the seroprevalence of influenza A(H9N2) infection among humans. J Infect Dis. 2015; 212: 562-569 Crossref PubMed Scopus (58) Google Scholar , implying that H9N2 viruses are poorly adapted in mammals. Cross-species incursions with the H9N2 subtype of AIV result in dead-end infections because the virus cannot adapt quickly enough in humans. Evidence shows that the amino acid residue at position 627 of the PB2 gene plays a major role in determining the host range and virulence(9). Statistical data have demonstrated that in nearly all human and avian influenza strains either a lysine (K) or glutamate (E), respectively, is present at that position. 1 Gu J. Gu M. Yan Y. Liu K. Wang X. Xu X. et al. Detection of PB2 627K mutation in two highly pathogenic isolates of the H7N9 subtype influenza A virus from chickens in northern China. J Infect. 2020; Abstract Full Text Full Text PDF Scopus (2) Google Scholar