{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:17:57Z","timestamp":1779891477495,"version":"3.53.1"},"reference-count":60,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T00:00:00Z","timestamp":1590019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Influenza viruses arise from animal reservoirs, and have the potential to cause pandemics. In 2013, low pathogenic novel avian influenza A(H7N9) viruses emerged in China, resulting from the reassortment of avian-origin viruses. Following evolutionary changes, highly pathogenic strains of avian influenza A(H7N9) viruses emerged in late 2016. Changes in pathogenicity and virulence of H7N9 viruses have been linked to potential mutations in the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA), as well as the viral polymerase basic protein 2 (PB2). Recognizing that effective viral transmission of the influenza A virus (IAV) between humans requires efficient attachment to the upper respiratory tract and replication through the viral polymerase complex, experimental evidence demonstrates the potential H7N9 has for increased binding affinity and replication, following specific amino acid substitutions in HA and PB2. Additionally, the deletion of extended amino acid sequences in the NA stalk length was shown to produce a significant increase in pathogenicity in mice. Research shows that significant changes in transmissibility, pathogenicity and virulence are possible after one or a few amino acid substitutions. This review aims to summarise key findings from that research. To date, all strains of H7N9 viruses remain restricted to avian reservoirs, with no evidence of sustained human-to-human transmission, although mutations in specific viral proteins reveal the efficacy with which these viruses could evolve into a highly virulent and infectious, human-to-human transmitted virus.<\/jats:p>","DOI":"10.3390\/microorganisms8050778","type":"journal-article","created":{"date-parts":[[2020,5,22]],"date-time":"2020-05-22T10:18:18Z","timestamp":1590142698000},"page":"778","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Evolution and Adaptation of the Avian H7N9 Virus into the Human Host"],"prefix":"10.3390","volume":"8","author":[{"given":"Andrew T.","family":"Bisset","sequence":"first","affiliation":[{"name":"School of Health Sciences, University of Notre Dame Australia, Fremantle WA 6160, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7370-9139","authenticated-orcid":false,"given":"Gerard F.","family":"Hoyne","sequence":"additional","affiliation":[{"name":"School of Health Sciences, University of Notre Dame Australia, Fremantle WA 6160, Australia"},{"name":"Institute for Health Research, University of Notre Dame Australia, Fremantle WA 6160, Australia"},{"name":"Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Nedlands WA 6009, Australia"},{"name":"School of Medical and Health Sciences, Edith Cowan University, Joondalup WA 6027, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1353\/bhm.2002.0022","article-title":"Updating the accounts: Global mortality of the 1918-1920 \u201cSpanish\u201d influenza pandemic","volume":"76","author":"Johnson","year":"2002","journal-title":"Bull. Hist. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1038\/emi.2014.9","article-title":"Host adaptation and transmission of influenza A viruses in mammals","volume":"3","author":"Schrauwen","year":"2014","journal-title":"Emerg. Microbes Infect."},{"key":"ref_3","unstructured":"(2019, February 16). World Health Organization. Available online: https:\/\/www.who.int\/en\/news-room\/fact-sheets\/detail\/influenza-(seasonal)."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1126\/science.1228172","article-title":"The structure of native influenza virion ribonucleoproteins","volume":"338","author":"Arranz","year":"2012","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1126\/science.1227270","article-title":"Organization of the influenza virus replication machinery","volume":"338","author":"Moeller","year":"2012","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41572-018-0002-y","article-title":"Influenza","volume":"4","author":"Krammer","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"D49","DOI":"10.1016\/j.vaccine.2008.07.039","article-title":"The biology of influenza viruses","volume":"26","author":"Bouvier","year":"2008","journal-title":"Vaccine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1099\/vir.0.2008\/004606-0","article-title":"The multifunctional NS1 protein of influenza A viruses","volume":"89","author":"Hale","year":"2008","journal-title":"J. Gen. Vir."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/emboj\/17.1.288","article-title":"The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins","volume":"17","author":"Talon","year":"1998","journal-title":"EMBO J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Steel, J., and Lowen, A.C. (2014). Influenza A virus reassortment. Influenza Pathogenesis and Control-Volume I, Springer.","DOI":"10.1007\/82_2014_395"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Domingo, E., and Perales, C. (2019). Viral quasispecies. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008271"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1128\/mr.56.1.152-179.1992","article-title":"Evolution and ecology of influenza A viruses","volume":"56","author":"Webster","year":"1992","journal-title":"Microbiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/82_2014_396","article-title":"Evolution and ecology of influenza A viruses","volume":"Volume 385","author":"Compans","year":"2014","journal-title":"Influenza Pathogenesis and Control-Volume I"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1099\/vir.0.044974-0","article-title":"Global transmission of influenza viruses from humans to swine","volume":"93","author":"Nelson","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12742","DOI":"10.1128\/JVI.05319-11","article-title":"Antigenic and genetic evolution of equine influenza A (H3N8) virus from 1968 to 2007","volume":"85","author":"Lewis","year":"2011","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1128\/JVI.77.5.3148-3156.2003","article-title":"Role of quail in the interspecies transmission of H9 influenza A viruses: Molecular changes on HA that correspond to adaptation from ducks to chickens","volume":"77","author":"Perez","year":"2003","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1126\/science.1117950","article-title":"Transmission of equine influenza virus to dogs","volume":"310","author":"Crawford","year":"2005","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/0042-6822(81)90200-2","article-title":"Characterization of an influenza A virus from seals","volume":"113","author":"Webster","year":"1981","journal-title":"Virology"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Munster, V.J., Baas, C., Lexmond, P., Waldenstr\u00f6m, J., Wallensten, A., Fransson, T., Rimmelzwaan, G.F., Beyer, W.E., Schutten, M., and Olsen, B. (2007). Spatial, temporal, and species variation in prevalence of influenza A viruses in wild migratory birds. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030061"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Tong, S., Zhu, X., Li, Y., Shi, M., Zhang, J., Bourgeois, M., Yang, H., Chen, X., Recuenco, S., and Gomez, J. (2013). New world bats harbor diverse influenza A viruses. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003657"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e01059-18","DOI":"10.1128\/JVI.01059-18","article-title":"Isolation and characterization of a distinct influenza A virus from Egyptian bats","volume":"93","author":"Kandeil","year":"2019","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2814","DOI":"10.1128\/JVI.79.5.2814-2822.2005","article-title":"Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls","volume":"79","author":"Fouchier","year":"2005","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1056\/NEJMoa1304459","article-title":"Human infection with a novel avian-origin influenza A (H7N9) virus","volume":"368","author":"Gao","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1038\/ncomms4142","article-title":"Dynamic reassortments and genetic heterogeneity of the human-infecting influenza A (H7N9) virus","volume":"5","author":"Cui","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.chom.2013.09.001","article-title":"Sequential reassortments underlie diverse influenza H7N9 genotypes in China","volume":"14","author":"Wu","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nature12515","article-title":"The genesis and source of the H7N9 influenza viruses causing human infections in China","volume":"502","author":"Lam","year":"2013","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nature14348","article-title":"Dissemination, divergence and establishment of H7N9 influenza viruses in China","volume":"522","author":"Lam","year":"2015","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11825","DOI":"10.1128\/JVI.74.24.11825-11831.2000","article-title":"Sialic acid species as a determinant of the host range of influenza A viruses","volume":"74","author":"Suzuki","year":"2000","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Matrosovich, M., Herrler, G., and Klenk, H.D. (2013). Sialic acid receptors of viruses. SialoGlyco Chemistry and Biology II, Springer.","DOI":"10.1007\/128_2013_466"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/440435a","article-title":"Avian flu: Influenza virus receptors in the human airway","volume":"440","author":"Shinya","year":"2006","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"De Vries, R.P., Peng, W., Grant, O.C., Thompson, A.J., Zhu, X., Bouwman, K.M., de la Pena, A.T.T., van Breemen, M.J., Wickramasinghe, I.N.A., and de Haan, C.A. (2017). Three mutations switch H7N9 influenza to human-type receptor specificity. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006390"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11300","DOI":"10.1038\/s41598-017-10749-5","article-title":"Adaptation of influenza A (H7N9) virus in primary human airway epithelial cells","volume":"7","author":"Huang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1016\/j.cell.2013.05.034","article-title":"Glycan receptor binding of the influenza A virus H7N9 hemagglutinin","volume":"153","author":"Tharakaraman","year":"2013","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1038\/ncomms2922","article-title":"Aerosol transmission is an important mode of influenza A virus spread","volume":"4","author":"Cowling","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/0165-6147(88)90154-X","article-title":"Binding of viral attachment protein to host-cell receptor: The Achilles heel of infectious viruses","volume":"9","author":"Lentz","year":"1988","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.1073\/pnas.0813172106","article-title":"Human HA and polymerase subunit PB2 proteins confer transmission of an avian influenza virus through the air","volume":"106","author":"Pappas","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1093\/cid\/ciy541","article-title":"Assessment of human-to-human transmissibility of avian influenza A (H7N9) virus across 5 waves by analyzing clusters of case patients in mainland China, 2013\u20132017","volume":"68","author":"Wang","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8153","DOI":"10.1128\/JVI.00894-14","article-title":"Analysis of recombinant H7N9 wild type and mutant viruses in pigs shows Q226L in HA is important for transmission","volume":"88","author":"Liu","year":"2014","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00375-18","DOI":"10.1128\/JVI.00375-18","article-title":"Structural and molecular characterization of the hemagglutinin from the fifth epidemic wave A (H7N9) influenza viruses","volume":"92","author":"Yang","year":"2018","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/j.1863-2378.2008.01217.x","article-title":"The role of swine in the generation of novel influenza viruses","volume":"56","author":"Ma","year":"2009","journal-title":"Zoonoses Public Health"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1126\/science.1243761","article-title":"Preferential recognition of avian-like receptors in human influenza A H7N9 viruses","volume":"342","author":"Xu","year":"2013","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1006\/viro.1994.1615","article-title":"Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates","volume":"205","author":"Connor","year":"1994","journal-title":"Virology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8502","DOI":"10.1128\/JVI.74.18.8502-8512.2000","article-title":"Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals","volume":"74","author":"Matrosovich","year":"2000","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.meegid.2017.09.027","article-title":"Evolutionary genotypes of influenza A (H7N9) viruses over five epidemic waves in China","volume":"55","author":"Ding","year":"2017","journal-title":"Infect. Genet. Evol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.3201\/eid2308.170600","article-title":"Human infection with highly pathogenic avian influenza A (H7N9) virus, China","volume":"23","author":"Ke","year":"2017","journal-title":"Emerg. Infect. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18590","DOI":"10.1073\/pnas.0507415102","article-title":"The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host","volume":"102","author":"Gabriel","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5278","DOI":"10.1128\/JVI.00063-09","article-title":"Selection of H5N1 influenza virus PB2 during replication in humans","volume":"83","author":"Le","year":"2009","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1126\/science.1062882","article-title":"Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses","volume":"293","author":"Hatta","year":"2001","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3568","DOI":"10.1128\/JVI.02740-13","article-title":"Amino acid substitutions in polymerase basic protein 2 gene contributes to the pathogenicity of the novel A\/H7N9 influenza virus in mammalian hosts","volume":"88","author":"Mok","year":"2014","journal-title":"J. Virol."},{"key":"ref_50","first-page":"11","article-title":"The PB2 mutation with lysine at 627 enhances the pathogenicity of avian influenza (H7N9) virus which belongs to a non-zoonotic lineage","volume":"7","author":"Li","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8039","DOI":"10.1038\/srep08039","article-title":"Amino acids substitutions in the PB2 protein of H7N9 influenza A viruses are important for virulence in mammalian hosts","volume":"5","author":"Yamayoshi","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"19474","DOI":"10.1038\/srep19474","article-title":"PB2-588 V promotes the mammalian adaptation of H10N8, H7N9 and H9N2 avian influenza viruses","volume":"6","author":"Xiao","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e02293-16","DOI":"10.1128\/JVI.02293-16","article-title":"Role of neuraminidase in influenza A (H7N9) receptor binding","volume":"91","author":"Benton","year":"2017","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e00049-17","DOI":"10.1128\/JVI.00049-17","article-title":"Mutation of the second sialic acid-binding site resulting in reduced neuraminidase activity preceded emergence of H7N9 influenza a virus","volume":"91","author":"Dai","year":"2017","journal-title":"J. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Guo, H., Rabouw, H., Slomp, A., Dai, M., van der Vegt, F., van Lent, J.W., McBride, R., Paulson, J.C., de Groot, R.J., and van Kuppeveld, F.J. (2018). Kinetic analysis of the influenza A virus HA\/NA balance reveals contribution of NA to virus-receptor binding and NA-dependent rolling on receptor-containing surfaces. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007233"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.3390\/ijerph120101020","article-title":"Could a deletion in neuraminidase stalk strengthen human tropism of the novel avian influenza virus H7N9 in China, 2013?","volume":"12","author":"Chen","year":"2015","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1128\/JVI.02553-15","article-title":"Changes in the length of the neuraminidase stalk region impact H7N9 virulence in mice","volume":"90","author":"Bi","year":"2016","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/rmv.352","article-title":"Functional balance between haemagglutinin and neuraminidase in influenza virus infections","volume":"12","author":"Wagner","year":"2002","journal-title":"Rev. Med. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4704","DOI":"10.1128\/JVI.01987-08","article-title":"Neuraminidase stalk length and additional glycosylation of the hemagglutinin influence the virulence of influenza H5N1 viruses for mice","volume":"83","author":"Matsuoka","year":"2009","journal-title":"J. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Zhou, H., Yu, Z., Hu, Y., Tu, J., Zou, W., Peng, Y., Zhu, J., Li, Y., Zhang, A., and Yu, Z. (2009). The special neuraminidase stalk-motif responsible for increased virulence and pathogenesis of H5N1 influenza A virus. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006277"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/8\/5\/778\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:31:20Z","timestamp":1760175080000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/8\/5\/778"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,21]]},"references-count":60,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["microorganisms8050778"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms8050778","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,21]]}}}