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We evaluated the infection and tropism of human and avian H9 influenza virus in the human respiratory tract using <jats:italic>ex vivo<\/jats:italic> respiratory organ culture. H9 viruses infected the upper and lower respiratory tract and the majority of H9 viruses had a decreased ability to release virus from the bronchus rather than the lung. This may be attributed to a weak neuraminidase (NA) cleavage of carbon-6-linked sialic acid (Sia) rather than carbon-3-linked Sia. The modified cleavage of N-acetlylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) by NA in H9 virus replication was observed by reverse genetics, and recombinant H9N2 viruses with amino acids (38KQ) deleted in the NA stalk, and changing the amino acid at position 431 from Proline-to-Lysine. Using recombinant H9 viruses previously evaluated in the ferret, we found that viruses which replicated well in the ferret did not replicate to the same extent in the human <jats:italic>ex vivo<\/jats:italic> cultures. The existing risk assessment models for H9N2 viruses in ferrets may not always have a strong correlation with the replication in the human upper respiratory tract. The inclusion of the human <jats:italic>ex vivo<\/jats:italic> cultures would further strengthen the future risk-assessment strategies.<\/jats:p>","DOI":"10.1038\/s41598-017-05853-5","type":"journal-article","created":{"date-parts":[[2017,7,18]],"date-time":"2017-07-18T07:52:37Z","timestamp":1500364357000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Replication of H9 influenza viruses in the human ex vivo respiratory tract, and the influence of neuraminidase on virus release"],"prefix":"10.1038","volume":"7","author":[{"given":"Renee W. Y.","family":"Chan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa L. Y.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris K. P.","family":"Mok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin P.","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adebimpe","family":"Obadan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C. W.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6569-5689","authenticated-orcid":false,"given":"Daniel R.","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. S. Malik","family":"Peiris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Nicholls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,24]]},"reference":[{"key":"5853_CR1","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.virol.2005.06.025","volume":"340","author":"C Li","year":"2005","unstructured":"Li, C. et al. Evolution of H9N2 influenza viruses from domestic poultry in Mainland China. Virology \n                           340, 70\u201383, doi:10.1016\/j.virol.2005.06.025 (2005).","journal-title":"Virology"},{"key":"5853_CR2","doi-asserted-by":"publisher","first-page":"8609","DOI":"10.1128\/JVI.78.16.8609-8614.2004","volume":"78","author":"YK Choi","year":"2004","unstructured":"Choi, Y. K. et al. Continuing evolution of H9N2 influenza viruses in Southeastern China. 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